Synthesis of Aromatic Heterocycles by Palladium(0

Synthesis of Aromatic Heterocycles by

Palladium(0)-Catalyzed Domino Reactions

and Cyclization of Hydrazone Dianions

Dissertation

zur

Erlangung des Doktorgrades

doctor rerum naturalium (Dr. rer. nat.)

der Mathematisch-Naturwissenschaftlichen Fakultät

der Universität Rostock

vorgelegt von

M.Sc. Thang Ngoc Ngo

geboren am 16 Oktober 1987 in Phu Tho, Vietnam

Rostock, 2016

zef007

Schreibmaschinentext

urn:nbn:de:gbv:28-diss2018-0035-1

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Die vorliegende Arbeit wurde im Institut für Chemie von April 2012 bis Dezember 2016

angefertigt.

Erster Gutachter Prof. Dr. Peter Langer

Institut für Chemie

Universität Rostock

Zweiter Gutachter Prof. Dr. Bernd Schmidt

Institut für Chemie

Universität Potsdam

Eingereicht am: 10. Oktober 2016

Tag der Verteidigung: 20. Dezember 2016

I

Acknowledgements

First and foremost, I would like to express my sincerest appreciation to Prof. Dr. Dr. h.c.

mult. Peter Langer for giving me the opportunity to be a part of his research group, for giving

me enthusiasm in chemistry, and for supervising me through difficulties during my PhD.

Without his guidance, support, and encouragement, I would never be able to achieve the work

in this dissertation.

I am deeply thankful to Dr. Dang Thanh Tuan and Dr. Tran Quang Hung for providing me

helpful suggestions and advice throughout my PhD. And I wish to express my special gratitude

to Dr. Peter Ehlers for his valuable support in the development of my work and his meticulous

correction of my dissertation.

I would like to express my acknowledgements to Professor Stefan Lochbrunner for his

support in photophysical characterization. And many thanks go to Mr. Wolfgang Breitsprecher

for his help with the absorption and fluorescence measurements. I wish to thank Dr. Jamshed

Iqbal for the biological studies, and his students, Sundas Sarwar, Syeda Abida Ejaz, Syeda

Mahwish Bakht, for conducting the biotests, Syed Jawad Ali Shah for molecular docking study.

My special thanks go to Dr. Dirk Michalik for NMR measurements and valuable

discussion, Dr. Alexander Vilinger for X-Ray measurements, Dr. Holger Feist and Dr. Martin

Hein for their tremendous support and advice, as well as Anna Hallman, Claudia Hahn, Carmen

Esser, and all other members of analytical and technical staffs of the Department of Chemistry,

University of Rostock and LIKAT (Leibniz-Institut für Katalyse).

I am honored to work with Dr. Omer Akrawi, Do Huy Hoang, Pham Ngo Nghia, Elina

Ausekle, and all other members of Professor Peter Langer’s research group in a friendly and

collaborative environment.

Many thanks go to Frank Janert and Stephan Wöhlbrandt for their diligent work during

their bachelor theses.

The financial support by the State of Mecklenburg-Vorpommern is gratefully

acknowledged.

Additionally, I wish to thank Prof. Dr. Dang Nhu Tai, Dr. Nguyen Quyet Chien, Dr. Tran

Thu Thuy, Dr. Pham Duy Nam, and Dr. Vuong Van Truong for their guidance in both chemistry

and life.

II

Finally, I would like to express the deepest thank for the love and encouragement of my

parents and my brother, especially my father, thank you for everything. And I would like to

thank my beloved wife for always being patient, and on my side through every step of life.

III

Declaration

Hereby I declare that this thesis has been written without any assistance from third parties.

Furthermore, I confirm that no sources have been used in the preparation of this thesis other

than those indicated in the thesis itself.

Erklärung

Hiermit erkläre ich, dass ich die vorliegende Arbeit selbstständig angefertigt und ohne

fremde Hilfe verfasst habe, keine außer den von mir angegebenen Hilfsmitteln und Quellen

dazu verwendet habe und die den benutzten Werken inhaltlich und wörtlich entnommenen

Stellen als solche kenntlich gemacht habe.

Rostock, September 2016

Thang N. Ngo

IV

Abstract

This dissertation focuses on the development of new and convenient synthetic approaches

for important or new aromatic heterocycles, which are potential for drug discovery and

advanced materials. Based on selective Pd(0)-catalyzed reactions of easily accessible starting

materials, the precursors with desired active centers were set up for further domino reactions

towards target molecules. This strategy was successfully applied in the development of new

synthetic methods for chromeno[3,4-b]pyrrol-4(3H)-ones, indolo[1,2-f]phenanthridines,

azaindolo[1,2-f]phenanthridines, and naphtho-fused heterocycles. Furthermore, a convenient

synthesis of fluorinated pyrazoles based on one-pot domino reaction of dianinons was

developed.

Zusammenfassung

Diese Dissertation beschäftigt sich mit der Entwicklung neuer und zugleich einfacher

synthetischer Zugänge von wichtigen bzw. neuen aromatischen Heterozyklen, welche von

Interesse für die Entwicklung neuer Wirkstoffe oder Materialien sind. Mittels selektiver Pd(0)

katalysierter Reaktionen von einfach zugänglichen Startmaterialien wurden Vorstufen

synthetisiert, welche im Anschluss durch Domino-Reaktionen zu den entsprechenden

Zielprodukten umgesetzt wurden. Diese Strategie wurde erfolgreich angewendet zur

Darstellung von Chromeno[3,4-b]pyrrol-4(3H)-onen, Indolo[1,2-f]phenanthridinen,

Azaindolo[1,2-f]phenanthridinen und Naphthalin-annellierten Heterozyklen. Außerdem wurde

ein praktischer Zugang zu fluorierten Pyrazolen, basierend auf einer Ein-Topf-Domino-

Reaktion entwickelt.

Table of Contents

Acknowledgements .............................................................................................................................. I

Declaration ......................................................................................................................................... III

Abstract .............................................................................................................................................. IV

List of abbreviations ..............................................................................................................................

1. General introduction ......................................................................................................................1

1.1. The importance of heterocycles ............................................................................................. 1

1.2. Palladium(0) catalytic cycle ................................................................................................... 4

1.2.1. Oxidative addition and reductive elimination .................................................................... 5

1.2.2. Reactions of Pd(II) complexes ........................................................................................... 7

1.2.3. Effects of ligands: Phosphine ligands .............................................................................. 16

1.3. Palladium(0)-catalyzed domino reactions in constructing important heterocycles.............. 18

1.4. The aim of dissertation ......................................................................................................... 21

2. Synthesis of pyrrolocoumarins via palladium(0)-catalyzed domino C-N

coupling/hydroamination reactions ....................................................................................................22

2.1. Introduction .......................................................................................................................... 22

2.2. Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones ................................................................. 24

2.3. Bioactivity and docking study.............................................................................................. 31

2.4. Conclusion ........................................................................................................................... 36

3. Palladium(0)-catalyzed domino C-N coupling/hydroamination/ C-H arylation reactions:

Synthesis of indolo[1,2-f]phenanthridines, azaindolo[1,2-f]phenanthridines .................................37

3.1. Introduction .......................................................................................................................... 37

3.2. Synthesis of indolo[1,2-f]phenanthridines ........................................................................... 39

3.3. Synthesis of azaindolo[1,2-f]phenanthridines ...................................................................... 48

3.4. Absorption and fluorescence properties of azaindolo[1,2-f]phenanthridines ...................... 59

3.5. Unsuccessful results ............................................................................................................. 60

3.6. Conclusion ........................................................................................................................... 63

4. Regioselective synthesis of naphtho-fused heterocycles via palladium(0)-catalyzed tandem

reaction of N-tosylhydrazones .............................................................................................................64

4.1. Introduction .......................................................................................................................... 64

4.2. Synthesis of naphtho-fused heterocycles ............................................................................. 66

4.3. Conclusion ........................................................................................................................... 76

5. Efficient one-pot synthesis of 5-perfluoroalkylpyrazoles by cyclization of hydrazone

dianions .................................................................................................................................................77

5.1. Introduction .......................................................................................................................... 77

5.2. Synthesis of perfluoroalkylated pyrazoles ........................................................................... 80

5.3. Alkaline phosphatase and nucleotide pyrophosphatase activity and SAR ........................... 86

5.4. Conclusion ........................................................................................................................... 88

APPENDIX ............................................................................................................................................. i

Methods for compound characterization and analysis ........................................................................ i

Biological protocols ..............................................................................................................................ii

Molecular docking ............................................................................................................................... vi

General procedure for the synthesis of pyrrolocoumarins ................................................................. vi

General procedure for synthesis of Indolo[1,2-f]phenanthridines ................................................... xvi

General procedure for synthesis of azaindolo[1,2-f]phenanthridines ........................................... xxvii

General procedure for domino reaction of dibromide compounds and N-tosylhydrazones .......xxxvii

General procedure for the synthesis of pyrazoles ......................................................................... xlviii

Crystal data and structure refinement ............................................................................................. lxix

List of tables .................................................................................................................................... lxxv

List of figures .................................................................................................................................. lxxvi

List of schemes .............................................................................................................................. lxxvii

List of References ........................................................................................................................... lxxix

List of abbreviations

°C Degrees Celsius

13C Carbon 13

19F Fluorine 19

1H Hydrogen, proton

Å Angstrom, 10-8 m

Ac Acetyl

AcO Acetate

Ar Aryl

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

Bn Benzyl

Boc N-tert-butoxycarbonyl

Calcd Calculated

CataCXium A Di(1-adamantyl)-n-butylphosphine

CI Chemical Ionization

cm-1 Wavenumber

Cy Cyclohexane

DavePhos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl

dba Dibenzylideneacetone

DMA Dimethylacetamide

DMF N,N-Dimethylformamide

DPEPhos (Oxydi-2,1-phenylene)bis(diphenylphosphine)

Dppe 1,2-Bis(diphenylphosphino)ethane

Dppf 1,1'- Bis(diphenylphosphanyl)ferrocene

EI Electron Ionization

EI-MS Electron Ionization - Mass Spectrometry

Equiv. Equivalent

ESI Electrospray Ionization

Et3N Triethylamine

GC Gas Chromatography

h Hour

HMBC Heteronuclear Multiple-bond Correlation Spectroscopy

HOMO Highest Occupied Molecular Orbital

HSQC Heteronuclear Single Quantum Coherence Spectroscopy

Hz Hertz (S-1)

IR Infrared Spectroscopy

J Coupling Constant

L Ligand

LCD Liquid Crystal Display

LUMO Lowest Unoccupied Molecular Orbital

m/z Mass-to-charge Ratio

MeCN Acetonitrile

mp Melting Point

MS Mass Spectrometry

NMR Nuclear Magnetic Resonance

NOESY Nuclear Overhauser Effect Spectroscopy

Nu Nucleophile

ORTEP Oak Ridge Thermal Ellipsoid Plot

OTf Triflate (Trifluoromethanesulfonate)

Ph Phenyl

PPh3 Triphenylphosphine

ppm Parts per Million

rt Room temperature

RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

Tf2O Trifluoromethanesulfonic anhydride

TFA Trifluoroacetic Acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TMS Trimethylsilane

UV/Vis Ultraviolet and visible absorption spectroscopy

XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

λ Wavelength

ϕ Fluorescence quantum yield

General Introduction

1

1. General introduction

1.1. The importance of heterocycles

Heterocyclic molecules could be figuratively compared to jewelry rings ornamented with

gemstones.[1] By introducing one or more heteroatoms to an aromatic carbocyclic system, both

chemical and physical properties change significantly, making the ring system more “precious”.

For example, pyridine, formed by replacing one CH unit in benzene by one nitrogen, could act

as a base or nucleophile while the α-hydrogens could undergo substitution by strong base such

as sodium amide. Another example is pyrrole, an electron-rich five-membered ring heterocycle,

formed by replacing two CH units in benzene by one NH unit, which is prone to electrophilic

reactions, or tend to be oxidized more easily. In addition, heteroatom that possesses one or more

unshared electron pairs, as of pyridine, imidazole, or pyrazole, can take part in weak interactions

such as hydrogen bonds or form complexes with metal ions, playing crucial roles in human

biological systems. Although activities of aromatic systems are improved by incorporation of

heteroatoms, the thermal stability is still retained in molecules of heteroaromatic systems.[1][2]


2

Figure 1.1: Heterocycles in hydrogen-bonding interaction and complex with metal cation

Aromatic heterocycles are ubiquitous in life and society and found crucial applications in

medicine, agriculture, and technology. From natural sources, a great number of heteroaromatic

compounds have been discovered and many of them have been used as drugs or lead

compounds for drug discovery. For instance, extracts from the bark of cinchona tree have been

used to prevent or cure malaria since 1632. Later studies showed that the main active component

of them is quinine, a quinoline derivative.[3] Quinine then was recommended as a first-line

treatment for malaria by WHO until 2006. Moreover, synthetic aromatic heterocycles also lead

to the discovery of many new drugs. For example, phenazone, known as an anti-inflammatory

and antipyretic drug, is a pyrazole derivative first synthesized by Lugwig Knorr in 1887.[4]


3

Figure 1.2: Aromatic heterocycles as drugs

Furthermore, synthetic aromatic polyheterocycles are essential components in developing

advanced materials. They are applied in numerous types of light-emitting diodes (OLEDs),

organic photovoltaic devices (OPVs), and organic field effect transistors (OFETs).[5]

Heteroatoms help improving stability, charge mobility, and molecular packing of aromatic

heterocycles over corresponding polycyclic aromatic hydrocarbons (PAHs).[6] For example,

pentacene, a linear PAH consisting of five fused benzene rings, known as an organic

semiconductor with high charge mobility, is vulnerable to oxidation, which slowly degrades

under air and light exposure; therefore, its applications is practically limited.[7] By introducing

heteroatoms to pentacene systems, the stability of obtained derivatives is improved as well as

other properties such as charge mobility, solubility, or molecular packing. Numerous pentacene

derivatives have been discovered by this strategy which possess potential electronic,

photophysical, and optical properties.[8] Moreover, heteroaromatic compounds can form

organometallic chelates with remarkable charge transport and luminescent properties. Among

them, Alq3 (tris(8-hydroxyquinolinato)aluminium), a common component of small molecule

OLEDs, has been used as the emission and electron transport layers.[9] And Ir(ppy)3

(Tris[2-phenylpyridinato-C2,N)iridium(III)), a green emitting complex, is used as the dopant in

phosphorescent organic light-emitting diode (PHOLED).[10]


4

Figure 1.3: Aromatic heterocycles applied in organic materials

Due to their gravity in modern life, extensive effort has been devoted to the development

of synthetic methods and characteristic studies of aromatic heterocycles. Recently, synthetic

methods of heterocyclic and polyheterocyclic compounds have been blooming in the light of

transition metal-catalyzed reactions.[11] Among them, palladium(0) – catalyzed reactions have

been well-studied and found important practical applications.[12–14]

1.2. Palladium(0) catalytic cycle

The chemistry of palladium(0)-catalyzed reaction was incubated in the late 1960s and has

been growing rapidly since then. Because of its practical importance to human life, in 2010, the

Nobel Prize in chemistry was dedicated to professors Heck, Negishi, and Suzuki for their

contribution to the development in the field.[15]

In general, a palladium(0)-catalyzed reaction is a catalytic cycle that includes 3 basic stages:

oxidative addition, reactions of Pd(II) complexes with appropriate nucleophiles, and reductive

elimination. Firstly, the catalytic cycle starts with a Pd(0) species that is oxidized by substrates

to generate a Pd(II) complex, which is called oxidative addition (OA). The new generated Pd(II)

species now behaves as an electrophile. Depending on the nature of nucleophiles, different

processes can take place, such as ligand substitution, transmetalation, or migratory insertion.

Finally, expected products are formed by reductive elimination (RE) of Pd(II) complexes, along


5

with the regeneration of [Pd(0)] catalyst to start a new catalytic cycle. In the case of migratory

insertion, the product and a hydridopalladium(II) halide complex are obtained after β-hydride

elimination, then the hydridopalladium(II) halide complex undergoes reductive elimination to

recreate the [Pd(0)] catalyst.[13,16]

Figure 1.4: A general Pd(0)-catalytic cycle

1.2.1. Oxidative addition and reductive elimination

Oxidative addition (OA) and reductive elimination (RE), which are microscopic reverse,

are involved in all Pd(0)-catalytic cycles.

Scheme 1.1: Oxidative addition and reductive elimination

The process above describes the oxidative addition of R-X to a Pd(0) center. After OA, both

coordination number and oxidative state of metal increase by 2 units. According to the

18-electron rule, Pd(0) with d10 configuration requires 8 more electrons to reach the

configuration of Xe, thus the coordination number of Pd(0) is four. For the oxidative addition

to occur, the metal center must have a lone pair of electrons and a vacant site, that means

16-electron or lower complex is required. For instance, a typical Pd(0) catalyst is Pd(PPh3)4;

before OA can be performed, at least one ligand (PPh3) must leave to activate the catalyst. As

studies have shown, a small amount of Pd(PPh3)2 was found in equilibrium with Pd(PPh3)3. The

two-coordinated species is more reactive than the three-coordinated complex and plays the main


6

role in oxidative addition. The highly active 14-electron Pd(0) species then performs OA with

the substrate, Pd(0) is oxidized to Pd(II) and the coordination number increases by two units,

resulting in a 16-electron square-planar Pd(II) complex, then isomerizes to the more stable trans

complex. Oxidative addition can undergo through 4 types of mechanisms: concerted,

substitution SN2, radical, or ionic mechanisms. In the case of aryl or vinyl halide (pseudohalide),

the mechanism oxidative addition to Pd(0) is widely accepted as concerted pathway for non-

polar substrates or substitution via SNAr for polar substrates.[16,17]

Scheme 1.2: Mechanisms of oxidative addition

Noteworthy, when the substrates contain two or more reactive centers for OA, controlling

the selectivity of OA is very important to obtained desired products. Generally, the rate of OA

for different halogens or pseudohalogens follows this trend: CAr-I > CAr-OTf > CAr- Br >>

CAr-Cl >>> CAr-F. CAr-F bonds, on the other hand, is relatively inert for OA. With a same

halogen, the electron density and steric effect of substituents around C-X decide the selectivity

of the reaction. OA favors less sterically hindered and more electron-positive carbon. For

example, by utilizing chemo-selectivity or site-selectivity on 2,3-dihalogenopyridine, different

products of cross-coupling reactions can be prepared depending on the synthetic strategy. Since

CAr-Br is more reactive than CAr-Cl, the first OA takes place at the 3rd position of

3-bromo-2-chloropyridine. However, with 2,3-dibromopyridine, the first OA takes place at the

2nd position which is more electron-positive.[18] Another demonstration is

5,7-dibromo-8-(trifluoromethylsulfonyloxy)quinolone. In this molecule, there are three

reactive centers for cross-coupling reactions, for example, Suzuki-Miyaura reaction. Evaluating

these three reactive centers, Br5 and Br7 are more reactive than OTf and Br5 is less sterically

hindered than Br7. Therefore, the reactivity order for OA is: C-Br5, C-Br7, and finally C-OTf.

[19] (figure 1.5)


7

Figure 1.5: Selectivity of oxidative addition on substrates with many reactive centers

Reductive elimination is the reverse of oxidative addition to regenerate Pd(0) catalyst from

Pd(II) complex, and in most cases, forms new bond in the product structure. Since RE is the

microscopic reverse of OA, RE can run through those mechanisms as OA, however, the most

important one is concerted pathway. Moreover, cis-coordination of the groups being eliminated

is required for RE. Therefore, in order for RE to perform, the trans Pd(II) complex must

isomerize to cis configuration. If a β-H is present in the molecular, β-hydride elimination may

compete with reductive elimination.

Reductive eliminations which involve H, such as H-H, H-R, H-COR, are particularly fast.

Reductive eliminations involving C(sp2)-C(sp2) bond formation usually take part in

cross-coupling reactions such as Suzuki-Miyaura, Negishi, Stills, Kumada, Hiyama couplings.

Sonogashira coupling, on the other hand, produces C(sp)-C(sp2) bond. Representative examples

for reductive elimination involving C(sp2)-N or C(sp2)-O bond formation are those of

Buchwald-Hartwig reaction.[20]

1.2.2. Reactions of Pd(II) complexes

As mentioned earlier, depending on the nature of nucleophiles interacting with the Pd(II)

complex, the catalytic cycle can run in different directions. Most important are ligand

substitution, demonstrated in Buchwald-Hartwig reaction, transmetalation in cross-coupling

reactions involving an organometallic reagent as the nucleophile, and migratory insertion in

Heck-type reactions or carbene insertion. Those transformations and their demonstration in

reactions utilized in this dissertation will be the main concern of this section.


8

Ligand substitution: Buchwald-Hartwig reaction

Ligand exchange is an important process for cross-coupling reactions involving

C-heteroatom bond formations such as C-N, C-S, C-O, C-P bonds.[21] One of the most important

reactions is Buchwald-Hartwig amination, in which amines are employed as nucleophiles.[22]

Scheme 1.3: Buchwald-Hartwig reaction

As described previously, the four-coordinated Pd(II) complex formed by OA is a 16-electron

square-planar complex. Ligand substitution of Pd(II) complexes can occur via two mechanisms:

associative pathway or dissociative pathway. In associative pathway, nucleophile forms a

penta-coordinated square-pyramidal Pd(II) complex by σ-bonding with empty pz orbital of Pd.

The 18-electron square-pyramidal complex then rearranges the configuration in which the

leaving ligand (usually X) is being on the top of the pyramid via a trigonal bipyramid

intermediate. Finally, the leaving ligand disassociates to form a new square-planar Pd(II)

complex. This process can be considered as an analog of SN2 reaction, in which Pd(II) center

is a soft electrophile. However, when the attack of nucleophile is sterically hindered or the

formation of penta-coordinated square-pyramidal complex is not favored by energy, ligand

exchange prefers via dissociative pathway. In this mechanism, the Pd-X bond is fully broken

to form a T-shaped intermediate, then the nucleophile attacks to the empty site left by X to form

the new square-planar complex. The dissociative pathway is similar to SN1 reaction. There is

no change in oxidation state at the Pd center through ligand substitution.


9

Scheme 1.4: Mechanisms of ligand exchange

Transmetalation: Suzuki and Sonogashira reaction

Scheme 1.5: Transmetalation

Transmetalation is an irreversible process involving the transfer of ligands from one metal

to another. Similar to ligand substitution, there is no change of oxidation state of the metal

centers. In this process, Pd(II) is an electrophilic center while R2-M bond is a nucleophile.

Therefore, increasing the nucleophilicity of R2 and electrophilicity of Pd(II) center accelerate

transmetalation. For transmetalation to proceed, Pd must be more electronegative than M. For

example, Pd(II) complexes participate in transmetalation with organometallic compounds of

metals such as Cu, B, Si, Zn, Al, Sn. Cross-coupling reactions involving transmetalation of

different organometallic reagents with Pd(II) complexes are summarized in figure 1.6.[23]


10

Figure 1.6: Cross-coupling reaction involving transmetalation

Among them, Suzuki-Miyaura cross-coupling reaction is one of the most popular methods

for constructing C(sp2)-C(sp2) bonds.[24] This method employs organoborons as the coupling

partner, which are easily accessible, air and moisture stable, less toxic, and safer for

environment than other organometallic compounds such as organostannane or organozinc.

Since the C-B bond is considered to be highly covalent, R2BX2 is a weak nucleophilic reagent.

Hence, to promote transmetalation, adding a nucleophile or base is often required to increase

the nucleophilicity of B-R2. In fact, many studies show that, without the presence of base,

organoboron compounds do not undergo transmetalation. A nucleophilic base can participate

in the reaction by two ways described in scheme 1.6. Following path A, organoboron compound

is activated by adding one base to the boron center, which is more readily to undergo

transmetalation. In path B, the nucleophilic base replaces X of Pd(II) complex and transforms

it to a new Pd(II) complex that is capable of coordinating to the boron center of organoborane.

The product of transmetalation then arranges to cis configuration for reductive elimination,

affording the product and regenerating Pd(0) catalyst.

Scheme 1.6: Roles of base in Suzuki-Miyaura reaction

While Suzuki-Miyaura reaction is widely used for constructing C(sp2)-C(sp2) bonds,

Sonogashira reaction is the most convenient method for forming C(sp2)-C(sp) bonds.[14,25] The

reaction utilizes organocopper compounds as the coupling partner, generated in situ from


11

terminal alkyne and CuX in the presence of an amine base. In this reaction, CuX is used as

catalytic amount, integrating with Pd cycle as shown in scheme 1.7.

Scheme 1.7: Mechanism of Sonogashira reaction

Insertion and elimination: Heck-type reactions and cross-coupling reactions of

N-tosylhydrazone

In organometallic chemistry, migratory insertion is an inserting process of a ligand to metal

complexes which results in bond formation of it with another ligand on the metal complex. By

that definition, migratory insertion of a ligand to Pd(II) complex can take place commonly in

two main ways: 1,1- and 1,2-migratory insertion. As depicted in scheme 1.8, 1,1-migratory

insertion results in bond formation of R with ligand X-Y at the same position with Pd while

1,2- migratory insertion gives bond at the neighboring atom.

Scheme 1.8: Migratory insertions


12

Ligands that have both donor and acceptor centers at the same atom usually undergo

1,1-migratory insertion. For example, CO gives 1,1-migratory insertion, in which both Pd and

R1 end up attached to carbon of CO.[26]

Scheme 1.9: Migratory insertion of CO

Scheme 1.10: Migratory insertion of carbene

Another important example is the migratory insertion of carbenes R2C, which possess a lone

pair electron that can act as a σ-donor and an empty orbital that can act as an acceptor at carbon

atom. Recently, the coupling reactions of aryl halide and diazo compound to synthesize

substituted olefins, in which carbene is generated in situ, have been attracting a lot of

attention.[27–29] Among them, cross-coupling reactions utilizing N-tosylhydrazone as the

coupling partner have been prove to be efficient to synthesized substituted olefins.[30,31] In this

reaction, under the high temperature and in the presence of a base, such as LiOtBu, a carbene

is generated in situ from N-tosylhydrazones.

Scheme 1.11: Cross-coupling reaction of N-tosylhydrazones involving carbene

On the other hand, 1,2-migratory insertion takes place when ƞ2-ligands, such as alkenes,

react with Pd(II) complexes. A typical example of 1,2-migratory insertion is the insertion of

double bond to Pd(II) complexes, an important step in Heck-Mizoroki cross-coupling

reaction.[32]


13

Scheme 1.12: Heck-Mizoroki reaction

Migratory insertion in Heck-Mizoroki reactions can undergo via three mechanisms: cationic,

neutral, or anionic pathways. Cationic mechanism takes place when Heck reactions of aryl

triflates or aryl halides are catalyzed by palladium-diphosphine in the presence of Ag(I) or Tl(I)

salts. Dissociation of OTf or X anion leaves Pd(II) center a positive charge and a vacant site,

that is attached by the double bond of an alkene. Then migratory insertion of double bond to

PdAr proceeds, forming new Pd(II) complex. During migratory insertion, both Pd-P bonds stay

intact so the enantioselectivity of the product can be achieved by utilizing chiral diphosphine

ligands.

Scheme 1.13: Cationic mechanism of 1,2-migratory insertion

Regularly, without the presence of Ag(I) or Tl(I) salt, migratory insertion of alkenes is

considered undergoing neutral pathway. This mechanism involves the dissociation of one

neutral ligand (phosphine ligand) to create a vacant site for the coordination of double bond

with Pd(II) center, leading to 1,2-migratory insertion of C=C to Ar-Pd.

Scheme 1.14: Neutral mechanism of 1,2-migratory insertion

Recent studies show that the combination of phosphine ligands and Pd(OAc)2 as precatalyst

may generate an anionic species [Pd(L)2OAc]- for oxidative addition of ArX, in which acetate

anion act as a bystander ligand. The product of oxidative addition is believed existing as a

penta-coordinated Pd(II) complex, which is short-live and easy to dissociate X- anion to form

neutral trans-ArPd(OAc)L2 as the key reactive intermediate. The reaction of this Pd(II) species


14

is the rate-determining step of the Heck reactions underwent anionic pathway. Acetate ligand

facilitates the dissociation of one phosphine ligand because of its bidentate nature.

Scheme 1.15: Anionic mechanism of 1,2-migratory insertion

In all three mechanisms, product of insertion is syn-addition of alkene to PdR. Regiochemistry

depends on the mechanism of insertion. Regioselectivity is under the influence of steric factor

when the reaction passes via neutral Pd complexes, which Ar prefer to attach to less hindered

carbon. On the other hand, regioselectivity is governed by electronic factor in mechanisms

involving cationic Pd complexes, which Ar favorably bonds with the less electron-density

carbon.

The reverse process of 1,2-migratory insertion, β-hydride elimination, is a process in which

a metal alkyl is converted to a hydro metal alkene complex. In order for β-hydride elimination

to process, a vacant site on Pd that is cis to the alkyl group is required, and Pd-C-C-H must

arrange on a coplanar conformation to bring β-H atom close enough to Pd to form an agostic

interaction. The Heck reaction is stereoselective for E olefin because the transition state of it is

more favored by energy. In addition, Z-configurated olefin, which is the minor product, can

react with H-Pd to form thermodynamically more stable E-isomer.

Scheme 1.16: β-hydride elimination

β-Hydride elimination produces olefin and hydridopalladium(II) halide complex, which

undergoes reductive elimination to regenerate Pd(0) catalyst.

An analogue of Heck reaction is the direct arylation of aryl halides and arenes without

pre-functionalized, affording biaryl compounds. This reaction has many advantages over

traditional cross-coupling reactions such as utilizing unactivated arenes instead of

pre-functionalized arenes for transmetalation.[33]


15

Scheme 1.17: C-H arylation vs traditional cross-coupling reactions

The reaction of Ar[Pd]X with arenes can be considered as electrophilic aromatic substitution

SEAr, Heck-like, or concerted metalation-deprotonation (CMD). Studies have supported that it

is reasonable to describe direct arylation of electron-rich, π-nucleophilic heteroarenes as SEAr

and that of electron-deficient benzenes as CMD.

Scheme 1.18: Mechanisms C-H arylation

Owning to the fact that there might be more than one C-H site in the structure of arene, more

than one biaryl products could be formed. In general, considering CMD pathway, the more

acidic the C-H bond, the more active it is in C-H activation reaction. On the other hand, the

Heck-like pathway favors the more stable intermediate, in which the positive charge is more

stabilized. Moreover, a strategy to achieve selectivity is to employ directing groups. Normally,

directing groups can coordinate to the Pd center, therefore limit it to a certain geometry, which

can selectively reach to the desired C-H site. For example, ester, amide, carbamate, nitro can

be used as directing groups, in which the ortho C-H to the directing group is usually the reacting

site. After the reaction, directing groups can be removed or transform to other functional

groups.[34]


16

Furthermore, intramolecular direct arylation is often utilized in constructing aromatic

polyheterocyles due to its convenience, which is important in developing synthetic methods in

this dissertation.[35]

Scheme 1.19: Intramolecular direct arylation

1.2.3. Effects of ligands: Phosphine ligands

Ligands are usually used in combination with Pd catalyst to achieve selectivity and

reactivity. In oxidative addition, Pd center of Pd(0) complexes acts as a nucleophile. Strong

σ-donating ligands such as alkyl phosphines and carbenes increase electron density at the Pd(0)

center; hence, facilitate oxidative addition. On the other hand, strong π-acceptor ligands such

as CO, however, slow the process down. Bulky ligands help pushing the equilibrium of Pd(0)

complexes to the two-coordinated 14-electron complex, or in some cases, generating

monoligated 12-electron complexes, which are highly active for OA. Bulky ligands also force

other ligands close together to facilitate reductive elimination. The Pd center of Pd(II)

complexes, on the other hand, is electrophilic and should be sterically accessible for the

incoming nucleophiles. Therefore, controlling the electronic and steric properties of ligands is

crucial for optimizing reaction conditions. In this dissertation, phosphine ligands were mainly

employed because of their availability and many advantages.

Phosphine ligands R3P, known as σ-donating and weak π-accepting ligands (d to σ* of

P-R), are widely used in Pd(0)-catalyzed cross-coupling reaction because they could be

conveniently synthesized in series. Furthermore, their electronic and steric properties could be

modified systematically and predictably by changing R. In addition, phosphines normally exist

in crystal form, are air and thermal stable. Therefore, they are easy to handle and stable under

a wide range of reaction conditions. Notably, in 1998, Fu reported a series of bulky,

electron-rich phosphines, such as P(tBu)3 and PCy3, used in combination with Pd(0)

precatalysts to produce biaryls from unactivated chloroarenes and arylboronic acid in good

yield.[36] At about the same time, Buchwald also reported comparable results with the discovery

of dialkyl biaryl phosphine ligands.[37] Those ligands have been applying widely in

Pd(0)-catalyzed C-C, C-N, C-O bond-forming reactions.[38]


17

Figure 1.7: Phosphine ligands

Moreover, Beller showed that turnover numbers of Suzuki-Miyaura couplings of unactivated

and deactivated chloroarenes could be achieved at 20000 when

di-(1-adamanyl)-n-butylphosphine (cataCXium® A) is used as the ligand.[39] Bulky ligands are

believed to promote the formation of highly active monoligated 12-electron Pd(0) catalyst.[40]

In addition, diphosphines such as Ph2P(CH2)nPPh2, which are bidentate ligands, also play an

important role in Pd-catalyzed reactions. This type of ligands force Pd(II) complexes to the cis

arrangement which accelerate both OA and RE. Bite angle is an important parameter regarding

bidentate ligands and easily modified combining with steric effect of substituents. Many studies


18

have shown that bidentate ligands with large bite angles have an impact on selectivity and

reactivity of the reaction.[41]

Figure 1.8: Diphosphine ligands

1.3. Palladium(0)-catalyzed domino reactions in constructing important heterocycles

Among synthetic approaches, methods that involve one-pot multistep reactions have been

proved to be effective, in which two or more reactions are carried out continuously without

isolating the intermediates. One-pot reactions bring several advantages over stepwise reactions

such as reduction in time, cost, and waste production. They help approaching complex

structures via more effective and shorter pathways, which are favored in industrial applications.

In particularly, if the reaction proceeds through many steps under the same reaction conditions

without adding additional reagents, the terms domino, cascade, tandem, or sequential catalysis

are used. Domino reactions can be classified as cationic, anionic, radical, pericyclic, transition

metal catalyzed, or enzymatic domino reaction.[42] Benefiting from the advance of transition

metal catalyzed reactions, especially Pd(0)-catalyzed reactions, a great number of

Pd(0)-catalyzed domino or one-pot reactions have been developed, providing practical tools for

construction of heteroaromatic systems.[43] Pd(0)-catalyzed domino reactions could be seen as

continuous Pd(0) catalytic cycles promoted by a single catalytic system. Some notable

examples will be discussed in following parts to demonstrate their utility.

One of the most important class of compounds which is present widely in biologically

active and naturally occurring compounds are indoles and indole-based structures.[44] In the

past, indoles were prepared by Fisher synthesis from phenylhydrazine and aldehyde or ketone


19

under acidic conditions. However, phenylhydrazine is very toxic, and the Fisher’s conditions

are somehow harsh. Later a lot of modifications have been studied to improve Fisher

synthesis,[45] such as Buchwald modification, in which involves Pd-catalyzed cross-coupling of

aryl bromide and hydrazones.[46]

Scheme 1.20: Approaches to the synthesis of indoles by Pd(0)-catalyzed domino reactions:

Recently, many convenient methods based on Pd(0)-catalyzed domino reactions have been

developed for the synthesis of indoles.[47] Among them, Larock’s method has proved to be

superior (a, figure 1.9).[48] The domino reaction initiates by oxidative addition of

2-halogenoaniline to form Pd(II) species, followed by regioselective insertion of alkyne to the

Pd(II) center, and subsequent intramolecular palladium displacement by amino group, affording

2,3-disubstituted indoles in good yields. A similar strategy starting

from ortho-alkynyltrifluoroacetanilides and aryl halides was reported by Cacchi (d).[49] The

methodology was well demonstrated in synthesizing the complex structure of

indolo[2,3-a]carbazole in a single step from 1,3-diaceylene precursor.[50]


20

Scheme 1.21: Synthesis of indolo[2,3-a]carbazoles by Cacchi

Starting from ortho-alkynylhalogenoarenes, Ackermann has combined Buchwald-hartwig

amination and intramolecular hydroamination to synthesize 2-substituted indoles with excellent

yields. Moreover, ortho-alkynylhalogenoarenes are easily obtained by Sonogashira reaction of

ortho-dihalogenoarenes and terminal alkynes (c).[51] Later, Ackemann has reported an

improvement that started straightforward from ortho-dihalogenoarenes, terminal alkyenes, and

amines in a one-pot three-component reaction.[52]

Scheme 1.22: Synthesis of indoles by one-pot three-component reaction by Ackemann

In addition, recently methods are also worth mentioning, for example, strategies that employ

aryl and alkenyl C-N bond formation (b)[53] or subsequently C-C and C-N bond formation from

imines and ortho-dihaloarenes (e).[54]

Furthermore, an important class of compounds derived from indole ring is carbazoles,

which are found in many natural alkaloids and some of them possess potential bioactivity.[55]

Carbazoles can be synthesized efficiently by Pd(0)-catalyzed domino reaction, for instance,

two-fold C-N bond formation by Buchwald-Hartwig reaction[56] or C-N and C-C bond

formation by subsequent Buchwald-Hartwig and C-H arylation reactions.[57]

Scheme 1.23: Approaches to the synthesis of carbazoles


21

1.4. The aim of dissertation

Motivated by the importance of aromatic heterocycles, the aim of this dissertation is to

develop new and convenient approaches for important or new aromatic heterocycles, mainly

nitrogen-containing. Compounds targeted in this work are potential for drug discovery and

advanced materials. Regarding biologically active compounds, the structures based on natural

products, which possess highly therapeutic activity, and drugs or novel drug candidates will be

explored. For discovering new organic material, aromatic polyheterocyclic compounds, which

have been proved to be crucial in advanced materials, will be the spotlight.

The synthetic methods developed for desired compounds are aiming to be convenient and

practical. My strategy is based on the selectivity of Pd(0)-catalyzed reactions of easily

accessible starting materials to set up the precursors with desired active centers for further

domino reactions. The precursors then will be converted to target molecules by designed

Pd(0)-catalyzed domino reactions. This strategy will be demonstrated throughout chapter 2 to

chapter 4. Chapter 5 is about domino reactions of dianions for the synthesis of fluorinated

compounds.

In addition, selected synthesized compounds will be submitted to biological studies in

collaboration with the group of Dr. Jamshed Iqbal (Centre for Advanced Drug Research,

COMSATS Institute of Information Technology, Abbottabad, Pakistan). And compounds with

potential application in developing advanced materials will be examined physical properties in

collaboration with the group of Prof. Stefan Lochbrunner (Institut für Physik, Universität

Rostock).

Palladium(0)-catalyzed Domino C-N Coupling/Hydroamination Reactions

22

2. Synthesis of pyrrolocoumarins via palladium(0)-catalyzed

domino C-N coupling/hydroamination reactions

2.1. Introduction

Pyrrolocoumarin is a privileged scaffold formulated from coumarin moiety fused with a

pyrrole unit which widely occurs in biologically active compounds. Notably,

chromeno[3,4-b]pyrrol-4(3H)-one, recognized as the core structure in molecules of marine

alkaloids ningalin B[58] and lamellarin,[59,60] exhibits potent pharmacological properties such as

immunomodulatory activity, cytotoxicity,[60] and HIV-1 integrase inhibition.[61] Some of them

are novel drug candidates or lead compounds for drug discovery. For example, synthetic

modification of lamellarin D leads to a series of Topoisomerase 1 inhibitors.[62]

Figure 2.1: Ningalin B and Lamellarin D derivatives

The diversity of their bioactivities has motivated many researches to develop efficient

synthetic routes for constructing the chromeno[3,4-b]pyrrol-4(3H)-one subunit. Generally,

there are two main strategies for the synthesis of this unique scaffold.[63] Firstly, synthesis of

chromeno[3,4-b]pyrrol-4(3H)-ones can be derived from regioselectively constructing

functionalized pyrrole moiety, following by lactonizing to afford the desired structure. This


23

approach is effectively demonstrated in the works of Iwao.[64] The second approach originated

from isoquinolines as starting materials.[65] Recently, synthesis of

chromeno[3,4-b]pyrrol-4(3H)-ones starting from coumarins has attracted a lot of attention. For

example, Langer group has reported a new approach to this scaffold by cyclocondensation

reactions of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin.[66]

Scheme 2.1: Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones

Moreover, catalytic hydroamination of alkynes has recently become a valuable synthetic

tool in the synthesis of fused nitrogen-containing heterocycles. Several catalytic systems have

been utilized for this type of cyclization such as palladium, gold, mercury, copper, zinc,

rhodium, platinum, indium, and iridium salts.[67] Among them, Pd(II) has been proved its

versatility. For example, Xu and co-workers reported an elegant approach to pyrrolocoumarins

by Pd-catalyzed intramolecular hydroamination of acetylenic aminocoumarins obtained from

4-chloro-3-nitrocoumarin.[68] Interestingly, Ackermann reported that the combination of

Pd(0)-catalyzed Buchwald-Hartwig amination and intramolecular hydroamination of

o-alkynylanilines with amines works harmoniously to form pyrrole-fused systems.[51,69]

Considering this strategy, I believe that it is plausible to obtain the pyrrolocoumarin framework

starting from a ortho-dihalogenated coumarin, following by mono-Sonogashira coupling

reaction to obtain key intermediate o-alkynyl bromocoumarin. The key step then relies on

forming fused-pyrrole ring via palladium catalyzed sequential C-N coupling/intramolecular

hydroamination of o-alkynyl bromocoumarins with amines. After reviewing many reported

synthetic approaches, I found that 3-bromo-4-(trifluoromethanesulfonyloxy)coumarin 2.3


24

would be the most suitable educt for synthesizing various analogues of pyrrolocoumarin

(scheme 2.3).

Scheme 2.2: Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones by hydroamination

2.2. Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones

Starting from commercially available 4-hydroxycoumarin 2.1, bromination was carried out

in MeCN at 20 °C by using NBS, affording brominated product 2.2 after 45 minutes with 91%

yield. 3-Bromo-4-hydroxycoumarin 2.2 was then easily transformed into its corresponding

triflate 2.3 by using triflic anhydride in dry DCM. Interestingly, the yield raised up from 55%

to 80% by reducing the temperature to -20 °C compared to 0 °C of the originally published

procedure (Scheme 2.3).[70]

Scheme 2.3: Synthesis of 3-bromo-4-(trifluoromethanesulfonyloxy)coumarin. Conditions: i,

NH4OAc, MeCN, 45 min, 20 °C. ii, 1 (1 equiv.), Tf2O (1.2 equiv.), Et3N (3 equiv.),

CH2Cl2, -20 °C to 20 °C.


25

Then, the selective Sonogashira cross-coupling reaction of

3-bromo-4-(trifluoromethanesulfonyloxy)coumarin 2.2 with phenylacetylene was studied as

the model reaction. Since C-OTf is more favored than C-Br in Sonogashira reaction plus the

C4 is more electron-positive than C3, the mono-coupling is expected at C4-OTf. At the first

attempt, the general procedure using Pd(PPh3)2Cl2/CuI in THF at room temperature (20 °C)

was applied, but the result was disappointing with only 7% yield of isolated product yield (entry

1, table 2.1). Only trace of product was detected when Pd(PPh3)4 was used as the catalyst (entry

2 and 3, table 2.1). After studying various conditions, Pd(CH3CN)2Cl2 proved to be the best

catalyst for this reaction so far. The reaction proceeded smoothly in NEt3/DMF (3:2) at room

temperature catalyzed by 5% of Pd(CH3CN)2Cl2 and 10% CuI in 75% yield (entry 7, table 2.1).

DMF must be added to overcome the low solubility of 2.3 in NEt3. Other attempts to raise the

temperature or to change the catalyst resulted in poor yields.

Table 2.1: Optimization for the synthesis of 2.4a

No. Catalyst (5 mol%),

CuI (10%) Base Solvent Time (h) Yield (%)

1 Pd(PPh3)2Cl2 NEt3 THF 4 7

2 Pd(PPh3)3 NEt3 THF 4 trace

3 Pd(PPh3)4 NEt3 CH3CN 4 trace

4 Pd(PPh3)2Cl2 NEt3 CH3CN 4 15

5 Pd(PPh3)2Cl2 NEt3 DMF 4 23

6 Pd(PPh3)2Cl2 DIPEA DMF 4 20

7 Pd(CH3CN)2Cl2 NEt3 DMF 2 75

Conditions: 2.3 (1 equiv.), alkyne (1.2 equiv.), NEt3/DMF (3:2), 20 °C

Applying the optimized conditions, I prepared various alkynylated coumarins 2.4b-g. Both

aromatic and aliphatic alkynes could be employed to achieve desired products (Table 2.2).


26

Table 2.2: Synthesis of 2.4

2.4 R1 Yield (%)

b

56

c

22

d

53

e

41

f CH3(CH2)2- 47

g CH3(CH2)3- 45

Conditions: 2.3 (1 equiv.), alkyne (1.2 equiv.), Pd(CH3CN)2Cl2 (5% mol),

CuI (10 % mol), NEt3/DMF (3:2), 20 °C, 2 h.

With the alkynylated coumarins in hand, the reaction of alkynylated coumarins 2.4 with

amines 2.5 affording pyrrolocoumarins 2.6 was investigated. Compound 2.4a and

4-methoxyaniline were firstly used as model substrates for the optimization of the reaction

conditions. During the studies, it became apparent that strong bases, such as NaOtBu or KOtBu,

should be avoided, because of decomposition of the coumarin ring under these conditions.

Therefore, mild inorganic bases, such as Cs2CO3, K2CO3, and K3PO4, were utilized. The

reaction was first studied in toluene as the solvent using Pd(OAc)2 (5%) as the catalytic source

and different phosphine ligands (10%). It is important to note that we could only obtain the

desired product, albeit in only 12% yield when SPhos

(2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) was used as the ligand and Cs2CO3 as the

base (entry 4, table 2.3). However, the yield could be improved when DMF or DMA was used

as the solvent. The best result (64% yield) was obtained when the catalyst loading was increased

to 10% and CuI (20%) was used as an additive (entry 14, table 2.3). The role of CuI might be

to promote the hydroamination step. The use of CuI as the catalyst in combination with ligands


27

also resulted in the formation of the product as well, however, only in 23% yield (entry 15, table

2.3).

Table 2.3: Optimization of 2.6a

No. Catalyst

(5%) Ligand (10%) Base Solvent

Temp.

(°C)

Time

(h)

Yield

(%)

1 Pd(OAc)2 XantPhosa Cs2CO3 Toluene 110 8 -

2 Pd(OAc)2 (tBu)3P·HBF4 Cs2CO3 Toluene 110 8 -

3 Pd(OAc)2 Cy3P Cs2CO3 Toluene 110 8 -

4 Pd(OAc)2 SPhos Cs2CO3 Toluene 110 8 12

5 Pd(OAc)2 XPhos Cs2CO3 Toluene 110 8 5

6 Pd(OAc)2 SPhos K3PO4 Toluene 110 8 -

7 Pd(OAc)2 SPhos K2CO3 Toluene 110 8 -

8 Pd(OAc)2 XPhos K3PO4 Toluene 110 8 -

9 Pd(OAc)2 XPhos K2CO3 Toluene 110 8 -

10 Pd(OAc)2 SPhos Cs2CO3 DMF 110 2 39

11 Pd(OAc)2 SPhos Cs2CO3 DMA 110 2 35

12 Pd(OAc)2 SPhos Cs2CO3 DMSO 110 8 -

13 Pd(OAc)2c SPhosb Cs2CO3 DMF 80 4 52

14 Pd(OAc)2

c

CuIb SPhosb Cs2CO3 DMF 80 4 64

15 CuIc 1,10-phenantrolineb Cs2CO3 DMF 110 8 23


28

16 CuIc 1H-Benzotriazole-1

-methanolb Cs2CO3 DMF 110 8 15

17 CuIc 1,2-DMEDAb Cs2CO3 DMF 110 8 17

18 CuIc TMEDAb Cs2CO3 DMF 110 8 11

Conditions: 2.4a (0.1 mmol, 1 equiv.), 2.5a (0.12 mmol, 1.2 equiv.), base (0.25 mmol,

2.5 equiv.), solvent 2 mL a5%, b20%, c10%

With the optimized conditions in hand, we extended the scope of the reaction to synthesize

a series of pyrrolocoumarins 2.6b-q using various amines (Table 2.4). The employment of

anilines containing electron donating substituents (more nucleophilic) generally resulted in

better yields than of anilines containing electron withdrawing groups. No product was isolated

from 4-nitroaniline. Aliphatic amines were successfully employed in the reactions, affording

desired products in good yields.

Table 2.4: Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones

Compound R1 R2 Structure Yield

(%)

2.6a

64

2.6b

47


29

2.6c

61

2.6d

52

2.6e

41

2.6f

35

2.6g

40

2.6h

82

2.6i

76


30

2.6j

61

2.6k

46

2.6l

57

2.6m

47

2.6n

65

2.6o

69


31

2.6p

62

2.6q

65

2.6r

51

Conditions: 2.4a-g (0.2 mmol, 1 equiv.), R’NH2 (0.24 mmol, 1.2 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol%), SPhos 0.04 (mmol, 20 mol%), Cs2CO3 (0.5 mmol, 2.5 equiv.), DMF (4 mL), 80 °C, 4 h.

The structures of all products were confirmed by spectroscopic methods. The structure of 2.6j

was independently confirmed by X-ray crystal structure analysis (Figure 2.2).

Figure 2.2: X-ray structure of 2.6j

2.3. Bioactivity and docking study

Synthesized compounds were tested for cholinesterase (acetylcholinesterase and

butyrylcholinesterase, obtained from electric eel and equine serum) and monoamine oxidase


32

(A & B) inhibition. Cholinesterase inhibition is known as one of the most powerful approaches

for the treatment of Alzheimer’s disease.[71] Moreover, monoamine oxidases are considered an

important therapeutic target for neurodegenerative disorders. Among them, selective MAO-A

inhibitors could be used as antidepressants and anxiolytics, and selective MAO-B inhibitors are

used for treatments of Parkinson's disease and Alzheimer's disease.[72] Interestingly, many

coumarin derivatives have been reported as potential inhibitors against both cholinesterases and

monoamine oxidases[73]. Therefore, chromeno[3,4-b]pyrrol-4(3H)-ones could be considered as

a potential approach to cholinesterase and monoamine oxidase inhibitors.

Table 2.5: Anticholinesterase activities of chromeno[3,4-b]pyrrol-4(3H)-ones

AcetylCholinesterase activity ButyrylCholinesterase activity

Compounds IC50±SEM (µM) IC50±SEM (µM)

2.6d 0.47±0.01 57.8±1.23

2.6e 11.8±0.99 82.1±2.45

2.6a 257.6±3.11 127.2±4.21

2.6f 2.87±0.56 159.1±3.11

2.6h 385.1±4.11 51.3±3.11

2.6i 0.47±0.01 208.8±2.56

2.6k 8.01±1.21 39.8±3.11

2.6q 248.7±4.89 14.9±2.16

2.6p 173.5±2.98 9.45±1.56

2.6m 308.7±3.12 34.1±1.78

2.6n 4.04±0.34 57.8±3.12

2.6l 16.8±1.56 18.4±1.89

2.6c 3.59±0.34 43.5±4.78

Donepezil 0.03 ± 0.01 6.41 ± 0.34

Neostigmine 22.2 ± 3.2 49.6 ± 6.11

As the results of anticholinesterase activity study (table 2.5), compounds 2.6d and 2.6i showed

highest inhibitory activity against AChE with the IC50 value of 0.47±0.01 µM. Structurally,

compound 2.6d contains phenyl group at C2 and N1 while 2.6i possesses phenyl group at C2

and phenethyl group at N1. Others modifications of the substituent at C2 and N1 lead to the

devaluation of inhibitory activity against AchE. Notably, the presence of aliphatic substituents,

methoxybenzyl at C2, or benzyl at N1 in the structure of chromeno[3,4-b]pyrrol-4(3H)-ones

significantly decreased the value of IC50 (compounds 2.6a, 2.6h, 2.6m, 2.6p, 2.6q). Compound

2.6i, however, exhibits lowest inhibitory activity against BChE, with the IC50 value of

208.8±2.56 µM. The most active BchE inhibitor was found to be compound 2.6p with the IC50

value of 9.45±1.56 µM. Furthermore, the data suggested that

chromeno[3,4-b]pyrrol-4(3H)-ones displayed selective inhibitory activity against either AChE

or BChE.


33

Table 2.6: Monoamine oxidase (A & B) activities of chromeno[3,4-b]pyrrol-4(3H)-ones

Compounds MA0-A

IC 50 µM & SEM VALUE

MAO-B

IC 50 µM & SEM VALUE

2.6d 0.79±0.005 0.33 ±0.06

2.6a 41% 43%

2.6b 0.77±0.003 2.18±0.03

2.6c 2.73±0.08 0.59±0.003

2.6f 1.09±0.01 4.71±0.05

2.6h 1.28±0.04 0.21±0.0005

2.6i 26% 11%

2.6j 0.53±0.001 15%

2.6k 1.21±0.02 40%

2.6q 1.51±0.03 37%

2.6p 5.12±0.07 0.15±0.0001

2.6m 0.69±0.0004 32%

2.6n 1.06±0.06 0.32±0.0002

2.6o 0.52±0.0003 21%

Clorgyline 3.64±0.012 -

Deprenyl - 0.007±0.001

Clorgyline were used as the standard inhibitor for monoamine oxidase A with IC50 value of

3.64±0.012 µM, and deprenyl for monoamine oxidase B with 0.007±0.001 µM. Compound 2.6j

and 2.6o were found to be potential inhibitors against monoamine oxidase A with IC50 value of

0.53±0.001 µM and 0.52±0.0003 µM respectively, which are about 7 times stronger compared

to the standard. Compound 2.6p, with IC50 = 0.15±0.0001 µM, exhibits the most effective

inhibitory activity against monoamine oxidase B among the tested

chromeno[3,4-b]pyrrol-4(3H)-ones. There is no clear trend between structure and monoamine

oxidase activities (table 2.6).

Compounds 2.6d and 2.6i showed similar activities against AChE, therefore these

compounds were chosen for molecular docking study. Both compounds show similar

interactions inside the receptor and form hydrophobic pocket with amino acid residues Trp279,

Ile287, Phe330, Phe33d1, Tyr334, and Gly335. However, the results showed that compound

2.6i established more stable conformation inside the receptor and formed additional hydrogen

bonds with two water molecules. Figure 2.3 shows the docked pose of 2.6i with AChE receptor

and Figure 2.4 shows interaction in 2D.


34

Figure 2.3: Putative binding mode of 2.6i inside AChE receptor (PDB ID 3I6Z).

The blue dashed lines indicate hydrophobic interactions of amino acids with phenyl groups of

the compound.

Figure 2.4: Putative binding mode of 2.6i inside AChE receptor (PDB ID 3I6Z).

Green solid line around the compound shows the hydrophobic layer of active site and the

dahed lines show hydrogen bonds with water molecule

Compound 2.6p was docked inside the active pocket of BuChE. The molecular docking

revealed that amino acid residues Gly16, Gly17, Ser198, Trp231, Leu286, Val288, Phe329, and

His438 formed weak hydrophobic bonding with 2.6p (figure 2.5). Additionally, carbonyl

moiety of compound 2.6p shows hydrogen bonding with amino group of amino acid residues

Ile199, Gly116, and Gly117 (figure 2.6).


35

Figure 2.5: Putative binding mode of 2.6p inside BuChE receptor (PDB ID 1P0I)

The blue dashed lines show the hydrophobic interactions of amino acid residues with phenyl

groups of compound 2.6p and the red dashed lines indicate hydrogen bonds between amino

group of Gly116, Gly117, Ala199 and carbonyl group of compound 2.6p.

Figure 2.6: Putative binding mode of 2.6p inside BuChE receptor (PDB ID 1P0I)

Green solid line around the compound shows the hydrophobic layer of active sites and the

dahed lines depict hydrogen bonds beteween carbonyl group of compound 2.6p with amino

groups of amino acid residues

After docking study, the docked poses were further verified by HYDE assessment. The ΔG

value for the compound 2.6i was calculated as -26 KJmol-1 while that of the 2.6h was only -10

KJmol-1. These results also prove the experimental data, which compound 2.6i is the best

inhibitor against AChE while compound 2.6h exhibit the least active inhibior. Similar results

were found in case of BuChE. The ΔG value for the strongest compound 2.6p is -18 KJmol-1

and for 2.6i is -15 KJmol-1.


36

2.4. Conclusion

A convenient method for the synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones was

successfully developed. Moreover, a series of chromeno[3,4-b]pyrrol-4(3H)-ones, which are

difficult to obtained by known methods, were prepared. New synthesized

chromeno[3,4-b]pyrrol-4(3H)-ones were studied regarding their inhibitory activity against

cholinesterases and monoamine oxidases. Among them, compounds 2.6d and 2.6i were found

to be potent selective inhibitors against AChE while compound 2.6p showed the best activity

as selective inhibitor against BuChE. Furthermore, chromeno[3,4-b]pyrrol-4(3H)-ones 2.6j and

2.6o also displayed potent inhibitory activity against monoamine oxidase A.

A part of the results of this chapter were published in:

T. N. Ngo, O. A. Akrawi, T. T. Dang, A. Villinger, P. Langer, Tetrahedron Lett. 2015, 56,

86–88.

Palladium(0)-Catalyzed Domino C-N Coupling/Hydroamination/ C-H Arylation Reactions

37

3. Palladium(0)-catalyzed domino C-N coupling/hydroamination/

C-H arylation reactions: Synthesis of indolo[1,2-f]phenanthridines,

azaindolo[1,2-f]phenanthridines

3.1. Introduction

Fused phenanthridines are recognized as an important motif among drug-like molecules

and found many applications in medicinal chemistry.[74] For example, nitidine, fagaronine, and

coralyne, which are natural alkaloids containing the benzo[c]phenanthridine moiety, possess

interesting antitumor activity and are important targets for total syntheses and biological

evaluations;[75] ethidium bromide, an intercalating agent, is used as a fluorescent tag;[76] and

pyrrolo[1,2-f]phenanthridines was found capable of inhibiting HIV (figure 3.1).[77]

Figure 3.1: Biologically active phenanthridines

In addition to their biological activities, due to their large π-conjugated electron system and

effects of heteroatom contributing to the conjugated system, fused phenanthridines are essential

components for developing new semiconductors and organic light-emitting diodes (OLEDs).[78]

Particularly, recent studies showed that fused phenanthridines possess interesting optical and

electronic properties, in which phenanthridines fused with N-heterocycles are potential

candidates for the development of new blue-emitting materials.[79] Furthermore, organic dyes

developed from indolo[1,2-f]phenanthridine structure show broad and intense visible

absorptions, which are promising new sensitizers for dye-sensitized solar cells (figure 3.2).[80]


38

Figure 3.2: Phenanthridine derivatives with potential physical properties

Although many methods for the synthesis of phenanthridines were developed in recent

years, most of them require many steps and/or harsh conditions, and even more challenging for

fused phenanthridines.[81] Therefore, developing new and efficient methods is important and

necessary for the development of new bioactive molecules and organic materials. In recent

years, the advances in transition metal-catalyzed reactions have facilitated considerably the

approach to complex structures. Among them, palladium-catalyzed domino reactions proved to

be a useful tool for the synthesis of fused heterocyclic compounds with high atom economy. In

2007, Zhang and coworkers published a convenient method to synthesize

indolo[1,2-f]phenanthridines by reaction of arynes with 1-(2-bromophenyl)-1H-indole in the

presence of a Pd catalyst.[82] However, approaching starting materials for this method could be

problematic and requires many synthetic steps. In 2012, Mirua et al. and later in 2013, You et

al. independently reported an interesting Pd-catalyzed domino N–H/C–H arylation for the

regioselective synthesis of N-heterocyclic fused phenanthridines.[83,84] These authors used

readily available 2-arylindoles and 1,2-dibromobenzene as the starting materials, however, the

selectivity of reactions was difficult to control, which may result in mixtures of isomers. A

similar cascade process involving C-H arylations followed by an intramolecular N-arylation

reaction to prepare benzimidazole-fused phenanthridines in moderate to good yields was

published by Peng et al. in 2014.[85] More recently, Wang and Lv reported a one-pot tandem

approach to indolo[1,2-f]phenanthridines employing 2-alkynylanilines and boronic acids via

Cu-catalyzed C-N coupling/hydroamination and Pd-catalyzed C-H arylation.[86]

Retrospectively, I believe that by combining intramolecular C-H arylation with the construction

of indole scaffold, fused phenanthridines could be formed in a one-pot domino reaction. For

constructing indole moiety, sequential Pd-catalyzed C-N coupling and intramolecular

hydroamination of ortho-halogenated phenylacetylene is expected to be most suitable in this

scenario.


39

Scheme 3.1: Domino reactions for the synthesis of fused-phenanthridines

In this chapter, I wish to describe a new synthetic methodology to efficiently approach

various indolo[1,2-f]phenathridines. The transformations proceed through three sequential

steps in a one-pot reaction: C-N coupling, hydroamination, and C-H arylation reactions with

employment of a single Pd catalyst. The reaction employs commercially available starting

materials: dihalogenated arenes, terminal alkynes, and 2-bromoanilines or anilines.

3.2. Synthesis of indolo[1,2-f]phenanthridines

For studying the reaction, 1-bromo-2-(phenylethynyl)benzene 3.1a and 2-bromoaniline

3.2a were chosen as model substrates. Initially, the reaction was carried out in DMF at 120 °C

using Cs2CO3 as the base in the absence of catalyst and ligand. However, the reaction did not

give the desired product 3.3a. When 10 mol% Pd(OAc)2 and 20 mol% PPh3 were introduced to

the reaction mixture as the catalyst, the product was isolated in 34% yield after 24 h. To improve

the yield, a series of monodentate and bidentate phosphine ligands were examined.

Consequently, XantPhos (10 mol%) and PCy3·HBF4 (20 mol%) were found to be the best

ligands as the reaction resulted in 75% and 74% yields of 3.3a, respectively. For further

investigation, other combinations of various palladium precursors and XantPhos were screened.

No product could be isolated when Pd2(dba)3 was used, while 70% yield of the desired product

was obtained when employing Pd(PPh3)4. It proved to be important to use Cs2CO3 as the base.


40

Only trace amounts of product were detected when other bases were used, such as K2CO3 and

KOtBu. Variation of solvent and temperature did not lead to improved yields (table 3.1).

Table 3.1: Optimization for the synthesis of 3.3a

Entry Catalyst Ligand Base Yield (%)

1 Pd(OAc)2 PPh3 Cs2CO3 34

2 Pd(OAc)2 BINAP Cs2CO3 34

3 Pd(OAc)2 XantPhos Cs2CO3 75

4 Pd(OAc)2 DPEPhos Cs2CO3 70

5 Pd(OAc)2 DPPE Cs2CO3 38

6 Pd(OAc)2 DPPF Cs2CO3 41

7 Pd(OAc)2 XPhos Cs2CO3 45

8 Pd(OAc)2 SPhos Cs2CO3 34

9 Pd(OAc)2 RuPhos Cs2CO3 38

10 Pd(OAc)2 DavePhos Cs2CO3 64

11 Pd(OAc)2 PCy3·HBF4 Cs2CO3 74

12 Pd(OAc)2 P(tBu)3·HBF4 Cs2CO3 5

13 Pd(PPh3)4 XantPhos Cs2CO3 70

14 Pd2(dba)3 XantPhos Cs2CO3 trace

15 Pd(OAc)2 XantPhos K2CO3 trace

16 Pd(OAc)2 XantPhos KOtBu 5

Conditions: 3.1a (0.1 mmol, 1 equiv.), 3.2a (0.12 mmol, 1.2 equiv.), Pd(OAc)2 (0.01 mmol,

10 mol%), ligand (20 mol% with monodentate ligands, 10 mol% with bidentate ligands),

Cs2CO3 (0.3 mmol, 3 equiv.), DMF (1 mL), 120 °C, 24 h.

With the optimized conditions in hand, I extended the scope of the reaction by modifying

both substrates to prepare a series of indolo[1,2-f]phenanthridines. First, several alkynes 3.1a-f

were synthesized by chemoselective Sonogashira coupling reactions of 2-bromo-iodobenzene

with 1.1 equiv. of various phenylacetylenes, including electron-withdrawing and -donating

substituents. These compounds were obtained in nearly quantitative yield when using reported

procedure.[87]


41

Table 3.2: Synthesis of alkynes 3.1

Compound R1 Structure Yield (%)

3.1a H

95

3.1b 4-Me

94

3.1c 4-tBu

92

3.1d 4-F

90

3.1e 4-OMe

96

3.1f 2-Br

74


42

Conditions: 2-bromo-iodobenzene 1 equiv., alkynes 1.1 equiv., Pd(PPh3)2Cl2 2.5 mol%,

CuI 10 mol%, Et3N is used as solvent and base, 25 °C, 4 h.

Then, reactions of 3.1a-e with 2-bromoanilline 3.2a, 2-bromo-4-methylaniline 3.2b, and

2-bromo-4-fluoroaniline 3.2c afforded various indolo[1,2-f]phenathridines 3.3 (Table 3.3). In

general, 1-bromo-2-(phenylethynyl)benzene or 2-bromoaniline derivatives, bearing

electron-donating or -withdrawing groups, afforded the corresponding products in moderate to

good yields under optimized conditions. The presence of substituents located at the aryl group

of the 1-bromo-2-(phenylethynyl)benzene had no pronounced effect on the yield. In contrast,

the structure of the 2-bromoaniline derivative had a greater impact, but did not follow a clear

trend. The best yields were obtained for 3.3h and 3.3j. The structure of 3.3i was unambiguously

confirmed by X-ray crystallography (figure 3.3).

Table 3.3: Synthesis of indolo[1,2-f]phenathridines

Compound R1 R2 Structure

Yield

(%)a

3.3a H (3.1a) H (3.2a)

75

3.3b H (3.1a) Me (3.2b)

66

3.3c Me (3.1b) H (3.2a)

52


43

3.3d Me (3.1b) Me (3.2b)

45

3.3e Me (3.1b) F (3.2c)

55

3.3f tBu (3.1c) H (3.2a)

65

3.3g tBu (3.1c) Me (3.2b)

67

3.3h F (3.1d) H (3.2a)

77

3.3i F (3.1d) Me (3.2b)

54

3.3j MeO (3.1e) H (3.2a)

78

3.3k MeO (3.1e) Me (3.2b)

73

Conditions: 3.1 (0.3 mmol, 1 equiv.), 3.2 (0.36 mmol, 1.2 equiv.), Pd(OAc)2 (0.03 mmol,

10 mol%), XantPhos (0.03 mmol, 10 mol%), Cs2CO3 (0.9 mmol, 3 equiv.), DMF (4 mL),

120 °C, 24 h.


44

Figure 3.3: X-ray crystal structure analysis of 3.3i

Moreover, I conducted additional experiments to study the applicability of less reactive

chlorine substituents in the reaction. I realized that the bromine substituent in acetylenes 3.1

played a crucial role in the reaction, since no conversion of 1-chloro-2-(phenylethynyl)benzene

was observed when reacting with 2-bromoaniline under the optimized conditions.

Scheme 3.2: Reaction of 1-chloro-2-(phenylethynyl)benzene with 2-bromoaniline

A possible mechanistic pathway of the formation of indolo[1,2-f]phenanthridines is proposed

in Scheme 3.3. First, a Buchwald-Hartwig reaction of 3.1b with 2-bromoaniline 3.2a gave

intermediate 3.1i. Intramolecular hydroamination of 3.1i subsequently formed intermediate

3.1ii (which could be isolated and structurally confirmed by NMR spectroscopy). Finally, an

intramolecular C-H activation took place to give indolo[1,2-f]phenanthridine 3.3c.


45

Scheme 3.3: Proposed pathway for the reaction

Encouraged by the successful isolation of intermediate 3.1ii, I considered the application

of 1,2-bis(2-bromophenyl)ethyne 3.1f as a suitable alternative precursor for the reaction. This

would allow the employment of simple anilines as educts and would widely broaden the scope

of the methodology. To my delight, the reaction of 1,2-bis(2-bromophenyl)ethyne 3.1f with

various anilines proceeded smoothly and produced the desired products 3.5a-j in moderate to

good yields (Table 3.4). Anilines containing a fluoro substituent gave very good results with

72% (3.5g) and 75% (3.5h) isolated yields. When employing an unsymmetrical aniline, a

mixture of two inseparable isomers 3.5e1 and 3.5e2 with 1:3 ratios was formed.


46

Table 3.4: Reaction of 1,2-bis(2-bromophenyl)ethyne 3.1f with amines

Compound R Products Yield (%)a

3.5a (3.3a) H (3.4a)

52

3.5b (3.3b) 4-Me (3.4b)

55

3.5c 4-tBu (3.4c)

43

3.5d 4-MeO (3.4d)

49

3.5e 3-MeO (3.4e)

43a

3.5f 2-MeO (3.4f)

49


47

3.5g 2-F (3.4g)

72

3.5h 4-F (3.4h)

75

3.5i 4-CN (3.4i)

44

3.5j 4-MeS (3.4j)

56

Conditions: 3.1f (0.3 mmol, 1equiv.), 3.4 (0.36 mmol, 1.2 equiv.), Pd(OAc)2 (0.03 mmol,

10 mol%), (PCy3·HBF4 0.06 mmol, 20 mol%), Cs2CO3 (0.9 mmol, 3 equiv.), DMF (4 mL),

120 °C, 24 h. a inseparable mixture (ratio 1:3 determined by NMR)

It is clear that employment of unsymmetrical dibromoacetylenes would result in a

selectivity issue. In order to address this problem, we investigated the reaction of

1-bromo-2-((2-chlorophenyl)ethynyl)benzene 3.1g containing two different halides. The

reaction of 3.1g with p-toluidine afforded, using the optimized conditions, the desired product

3.5b in only 14% yield. As mentioned before, no conversion takes place in the reaction of

1-chloro-2-(phenylethynyl)benzene with 2-bromoaniline under the same conditions. Therefore,

the reactions were assumed to proceed starting from Buchwald Hartwig reaction at the C-Br

bond, followed by hydroamination and intramolecular C-H arylation at the C-Cl bond (scheme

3.4).


48

Scheme 3.4: Reaction of 1-bromo-2-((2-chlorophenyl)ethynyl)benzene with p-toluidine

3.3. Synthesis of azaindolo[1,2-f]phenanthridines

As mentioned previously, the structure obtained when phenanthridine fused with

N-heterocycles, such as imidazole, benzoimidazole, indole, and pyrrole, were reported to

possess remarkable optical and electronic properties. For example, phenanthridine fused with

N-heterocycles, such as imidazole, benzoimidazole, indole, and pyrrole, were reported to

possess remarkable optical and electronic properties.[79,83,85] Moreover, azaindoles are also

considered as important core structures and have been studied for decades.[88] However, the

scaffold of phenanthridine fused with azaindole is rarely reported, probably because of

difficulties in synthetic approaches. To my best knowledge, only one work (patented) related

to azaindolo[1,2-f]phenanthridines was published (figure 3.4); authors of the patent claimed

that electroluminescent devices employing these compounds showed improvement in driving

voltage and lifespan in comparison of using Alq3.[89] Therefore, developing an efficient

synthetic method for this scaffold is compelling for further studies of its properties.

Figure 3.4: Azaindolo[1,2-f]phenanthridines applicable in electroluminescent devices

In the reported patent, authors synthesized azaindolo[1,2-f]phenanthridine scaffold starting

from 7-azaindole, following by Ullmann reaction to obtain the key intermediate. This precursor

was transformed to azaindolo[1,2-f]phenanthridine by Pd-catalyzed cascade reaction with

benzyne generated in situ from 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, which was

mentioned in previous part (scheme 3.5).


49

Scheme 3.5: Synthesis of azaindolo[1,2-f]phenanthridines via in situ benzyme

Regarding my methodology for the synthesis of fused phenanthridines, the strategy relies

on three sequential steps catalyzed by a single Pd catalyst in a one-pot reaction: C-N coupling,

hydroamination and intramolecular C-H arylation. After contemplation, I realized that this

strategy could be applied efficiently to synthesize phenanthridines-fused azaindole scaffolds

from simple and commercially available dihalogentated pyridines. Especially by employing

chemo- or regioselective of Sonogashira reaction for modifying the alkyne precursors, different

scaffolds, 4- or 7-azaindolo[1,2-f]phenanthridines, could be obtained (scheme 3.6).

Scheme 3.6: Synthesis of azaindolo[1,2-f]phenanthridines

In the following section, the details will be discussed, and furthermore, the optical properties

of selected synthesized compounds will be studied to justify the objective of the proposed idea.

Initially, 3-bromo-2-(phenylethynyl)pyridines 3.6a and 2-bromoaniline were chosen as

model substrates to study the reaction. No desired product was obtained after stirring the

mixture of substrates and cesium carbonate in DMF at 120 °C for 24 h. At the beginning, we

applied the reaction conditions from the previous reactions (table 3.3), which utilizes

Pd(OAc)2/XantPhos as the catalytic system. Interestingly, these conditions produced the

desired product with 39% yield. Furthermore, when the reaction time was increased to 48 h, the

yield of the reaction raised to 64%. Encouraged by this result, we continued to investigate other

combinations of catalytic sources and ligands using the same solvent, base, and temperature


50

conditions. To my delight, XantPhos was the best choice of ligand so far. The combination of

Pd(PPh3)4 and XantPhos gave the best result with 68% yield. Other attempts to change the

solvent and base did not lead to higher yields. Notably, decreasing the reaction temperature also

led to a significant decrease of yield. During the reaction, we observed the formation of

intermediate 3.6ii as a potential intermediate of the reaction pathway which is proposed in

Scheme 3.7.

Scheme 3.7: Proposed pathway for the reaction

With the optimized conditions in hand, the scope of the reaction was extended by

modifying the starting alkynes and 2-bromoanilines. Both electron-withdrawing and

electron-donating substituents were introduced into both substrates. Firstly,

3-bromo-2-(alkynyl)pyridines 3.6a-3.6f were synthesized from 2,3-dibromopyridine by

selective Sonogashira reaction at its C2, affording desired compounds with good to excellent

yields (table 3.5).


51

Table 3.5: Synthesis of 3-bromo-2-(alkynyl)pyridines


3.6a H

86

3.6b 4-Me

91

3.6c 4-tBu

95

3.6d 4-F

80

3.6e 4-OMe

91

3.6f 2-Br

77


52

Conditions: 2,3-dibromopyridine 1 equiv., alkynes 1.1 equiv., Pd(PPh3)2Cl2 2.5 mol%, CuI

10 mol%, Et3N is used as solvent and base, 25 °C, 4 h.

Then the domino reactions were performed with obtained 3-bromo-2-(alkynyl)pyridines

and several anilines. The reaction proceeded smoothly with various starting materials under

optimized conditions affording the desired products 3.7a-3.7k in moderate to high yields.

However, no apparent effect of the substituents on the yield was observed. Compound 3.7h was

obtained with the highest yield (88%) (Table 3.6). Furthermore, the structure of 3.7j was

independently confirmed by X-ray crystallographic analysis (figure 3.5).

Table 3.6: Synthesis of 4-azaindolo[1,2-f]phenanthridines

Compound R1 R2 Structure Yield (%)a

3.7a H H

68

3.7b H Me

64

3.7c H F

41


53

3.7d Me H

61

3.7e Me Me

72

3.7f tBu H

69

3.7g tBu Me

32

3.7h F H

88

3.7i F Me

79


54

3.7j MeO H

85

3.7k MeO Me

37

Conditions: 3.6 (0.3 mmol, 1 equiv.), 3.2 (0.36 mmol, 1.2 equiv.), Pd(PPh3)4 (0.03 mmol,


120 °C, 24 h.

Figure 3.5: X-ray crystallographic analysis of 3.7j.

Similarly, I assumed that the position of bromine and hydrogen atom participating in the

last step of the reaction could be interchangeable. With this idea in mind, reactions of 3.6f with

various amines were investigated to broaden the scope of this strategy (table 3.7).


55



3.8a (3.7a) H (3.4a)

87

3.8b 4-MeO (3.4d)

51

3.8c 2-MeO (3.4f)

60

3.8d 3-MeO (3.4e)

65 (mixture)


56

3.8e (3.7c) 4-F (3.4g)

76

3.8f (3.7b) 4-CH3 (3.4b)

65

3.8g 4-SMe (3.4j)

81

3.8h

(3.4k)

42

Conditions: 3.6f (0.3 mmol), 3.4 (0.36 mmol), Pd(PPh3)4 (0.03 mmol), XantPhos

(0.03 mmol), Cs2CO3 (0.9 mmol), DMF (4 mL), 120 °C, 24 h.

To my delight, the reaction proceeded without any problem when the same conditions as

in the previous reaction were applied, affording desired products in moderate to high yields.

Interestingly, compounds 3.7a (3.8a), 3.7b (3.8f), 3.7c (3.8e) could be synthesized by this

method with higher yield. Besides, other modifications on the aniline ring gave lower yields

compared to 2-bromoanline. However, the limitation of this method is the selectivity when

meta-substituted amines are used, such as 3-methoxyaniline 3.4e. In this case, using

3-methoxyaniline resulted in a mixture of two products, which were not separable by column

chromatography.


57

Additionally, the selectivity of the Sonogashira reaction on halogenated pyridines gives us

the possibility to deliver a higher diversity of products by customizing the starting material. To

demonstrate this, the selective Sonogashira mono-coupling reaction of

1-chloro-2-ethynylbenzene on 3-bromo-2-chloropyridine was performed to afford alkyne 3.6g.

The coupling reaction of 3-bromo-2-chloropyridine is controlled by the chemoselectivity of

bromide at position 3 versus the chloride at position 2, compared to 2,3-dibromopyridine in

which reactions at position 2 are more favored. Subsequently, alkyne 3.6g produced various

7-azaindolo[1,2-f]phenanthridines 3.9a-3.9c under optimized conditions as shown in table 3.8.

Noteworthy, the C2-Cl of 3.6g (of pyridine ring) is more reactive than of

1-chloro-2-(phenylethynyl)benzene for the first step of the domino reaction (Buchwald-

Hartwig reaction), as 1-chloro-2-(phenylethynyl)benzene showed no conversion when applied

conditions to perform the domino reaction (scheme 3.2).

Scheme 3.8: Synthesis of 3.6g


Compound R Structure Yield (%)a

3.9a 4-MeO (3.4d)

34


58

3.9b 4-F (3.4g)

51

3.9c 4-SMe (3.4j)

36

Conditions: 3.6g (0.3 mmol, 1 equiv.), 3.4 (0.36 mmol, 1.2 equiv.), Pd(PPh3)4 (0.03 mmol,


120 °C, 24 h. (temperature and reaction time were not optimized)

To explore larger conjugated systems, I considered structure 3.10 (scheme 3.9) as the target

of the domino reaction. Then, 2,3,5,6-tetrabromopyridine was utilized as the starting material,

affording product of selective two-fold Sonogashira reaction at 2 and 6 positions as the set-up

for the domino reaction. Unfortunately, the reaction resulted in an inseparable mixture.

Scheme 3.9: Two-fold domino reaction


59

3.4. Absorption and fluorescence properties of azaindolo[1,2-f]phenanthridines

The optical properties of all synthesized compounds were studied by UV/Vis and

fluorescence spectroscopy in CH2Cl2 at 25 °C as summarized in table 3.9. The UV/Vis spectra

show an absorption band in the range of 270-300 nm and several weaker bands in the range of

300-400 nm (figure 3.6). In general, introducing electron-donor groups, such as a methyl or

methoxy group, at the core structure 3.7a causes a slight red shift of the absorption bands. A

stronger redshift was observed for compound 3.8h by extending the conjugated system of the

core structure. Changing the position of the nitrogen atom in the azaindole moiety (compounds

3.9a, 3.9b, 3.9c) caused also a shift to longer wavelengths. The similar trend was also observed

in the emission spectra.

Figure 3.6: Normalized absorption and corrected emission spectra of

azaindolo[1,2-f]phenanthridines in CH2Cl2.


60

Table 3.9: Absorption and emission spectroscopic data of azaindolo[1,2-f]phenanthridines

Cp λabs1

Log

ε(λabs1)

λabs2

(nm)

Log

ε(λabs2)

λabs3

(nm)

Log

ε(λabs3)

λabs4

(nm)

Log

ε(λabs4)

λabs5

(nm)

Log

ε(λabs5)

λem

max

(nm)

Փfluo

%

3.7a 290 6.347 326 5.937 354 5.744 370 5.777 390 5.623 416 65

3.7d 292 6.598 328 6.251 355 6.098 371 6.100 391 5.978 420 42

3.7f 292 6.729 327 6.349 354 6.178 371 6.196 390 6.054 420 53

3.7h 290 6.614 327 6.296 355 6.105 371 6.065 391 5.872 424 28

3.7j 296 6.554 329 6.287 359 6.121 373 6.059 391 5.836 431 47

3.7b 290 6.576 329 6.214 356 5.953 374 5.984 394 5.860 421 52

3.7e 292 6.647 330 6.308 357 6.039 374 6.072 394 5.916 424 56

3.7g 292 6.649 330 6.301 375 6.041 374 6.069 394 5.929 425 55

3.7i 289 6.469 327 6.233 356 6.122 371 6.105 390 6.011 424 14

3.7k 296 6.338 332 6.115 360 5.893 375 5.819 396 5.702 435 32

3.8b 282 6.503 334 6.234 361 5.947 380 5.946 400 5.858 432 28

3.8c 290 6.645 330 6.288 - - 368 6.010 385 5.832 420 28

3.8e 289 6.581 329 6.363 357 6.049 375 6.036 395 5.871 425 38

3.8g 289 6.567 338 6.203 - - 375 5.994 - - 434 12

3.8h 281 6.646 - - 374 5.897 396 5.735 418 5.530 459 19

3.9a 282 6.785 331 6.060 364 6.060 380 6.063 400 5.930 433 40

3.9b 278 6.649 326 6.416 358 6.056 375 6.027 395 5.858 426 30

3.9c 288 6.845 337 6.337 363 6.018 376 5.993 400 5.785 436 26

Fluorescence spectra of the compounds were measured in CH2Cl2 exciting them at 360 nm.

The spectra show maximal emission in the range of 416 nm to 469 nm. Emission quantum

yields were determined using a solution of quinine hemisulfate salt monohydrate in 0.05 M

H2SO4 (Փ = 0.52) as a reference standard.[90] Among the synthesized compounds,

4-azaindolo[1,2-f]phenanthridine 3.7a, which contains no substituent, possesses the highest

quantum yield of 65%. In addition, 7-azaindolo[1,2-f]phenanthridine 3.9a also exhibit a good

quantum yield of 40%. Noteworthy, the quantum yield of indolo[1,2-f]phenanthridine was

reported to be only 21%.[83] Therefore, introducing one more nitrogen atom to the scaffold of

indolo[1,2-f]phenanthridine to obtain azaindolo[1,2-f]phenanthridines gives a much better

result. However, introducing both electron-donating and electron-withdrawing groups to the

core structure leads to decreased quantum yields. The poorest quantum yield of 12% was

observed in compound 3.8g which contains a methylthio group.

3.5. Unsuccessful results

Attempt to total synthesis of arnoamine C, D, and their derivatives

Recently, the search for new pharmaceuticals from the marine environment has resulted in

the isolation of a large number of alkaloids. In 2013, arnoamine C and D, which contain a

pentacyclic unit, were isolated from Cystodytes violatinctus and showed interesting anticancer

activities. IC50 values of arnoamine D are less than 10 μM in the presence of HCT116, SW480,


61

and A375 cancer cell lines.[91] Derivatives of Arnoamine C & D would have interesting

bioactivities for applications in medicinal chemistry.

Figure 3.7: Arnoamine C & D

Based on the same strategy described in scheme 3.1, the total synthesis of Arnoamine C &

D and their derivatives could be synthesized using three-step domino reaction (scheme 3.11).

Scheme 3.10: Retrosynthesis analysis of Arnoamines

The starting material 3.11 can be synthesized from 5-chloro-2-methoxyaniline via 3 steps in

scheme 3.11.[92]


62

Scheme 3.11: Proposed Synthesis of starting material

However, the precursor 3.11 failed to convert to corresponding desired compound 3.10. I

assumed that chlorine might be not reactive enough for the reaction; therefor, another starting

material containing bromine was employed. For this purpose, 6-hydroxyquinoline was used as

the starting point, following by bromination with NBS and triflation to obtain

5-bromo-6-trifluoromethanesulfonatequinoline 3.12. Selective Sonogashira at the C-OTf of

quinoline 3.12 was performed successfully, affording precursor 3.13 for the domino reaction.

Scheme 3.12: Alternative starting material 3.13

With the initial screening, the formation of desired product was observed together with the

intermediate by GC/MS. But unfortunately, the desired product 3.14 was not separable as the

pure product.


63

Scheme 3.13: Domino reaction of 3.13

3.6. Conclusion

In conclusion, two Pd-catalyzed three-step tandem reactions comprising of the three

sequential reactions: C-N coupling, hydroamination and C-H arylation reaction were

developed. These methods offer a straightforward synthesis of indolo[1,2-f]phenanthridines

under mild conditions with good yields, which are interesting for further applications in the

synthesis of new organic materials and bioactive molecules. In addition, a series of new

azaindolo[1,2-f]phenanthridines were synthesized conveniently by this strategy. The starting

materials were easily accessible by regioselective Sonogashira cross-coupling reaction, which

lead to diverse final products. The absorption and fluorescence properties of all products were

studied. This class of compounds shows promising photophysical properties, in particular, high

quantum yields. Furthermore, other new aromatic polyheterocycles are being explored by the

developed synthetic method.

The results of this chapter were published in:

T. N. Ngo, P. Ehlers, T. T. Dang, A. Villinger, P. Langer, Org. Biomol. Chem. 2015, 13,

3321–3330. Highlighted in Synfacts S001815SF.

and

T. N. Ngo, F. Janert, P. Ehlers, D. H. Hoang, T. T. Dang, A. Villinger, S. Lochbrunner, P.

Langer, Org. Biomol. Chem. 2016, 14, 1293–1301.

Palladium(0)-Catalyzed Tandem Reaction of N-Tosylhydrazones

64

4. Regioselective synthesis of naphtho-fused heterocycles via

palladium(0)-catalyzed tandem reaction of N-tosylhydrazones

4.1. Introduction

Since its first discovery, independently by Mizoroki and Heck, Heck-Mizoroki reaction is

among the most useful synthetic tools due to its high chemoselectivity, mild reaction conditions,

and cheap reaction reagents.[93] Especially, domino processes involving intramolecular

Heck-Mizoroki reaction have been known as one of the most powerful methods to produce

polycarbocyclic or polyheterocyclic compounds with a variety of ring sizes. The active alkyl

intermediate palladium complexes, formed by insertion of double bond to Pd(II) complex, can

participate in sequential intra- or intermolecular processes before the β-hydride elimination

step[94]. For example, the active intermediate alkyl palladium complex could react with another

double bond in the molecule to afford fused bicyclic compounds.[95] Moreover, regioselectivity

in intramolecular Heck reaction has also attracted a lot of attention. Generally, intramolecular

Heck reactions give exo-trig cyclization products, however, several reactions formed

6-endo-trig instead of 5-exo-trig cyclized products.[96] In some cases, the 6-membered ring

might be the result of a sequence of 5-exo-trig, then 3-exo-trig cyclization, finally ring opening

of cyclopropane (Scheme 4.1). If the β-hydride elimination occurs before the ring opening

process, the cyclopropane ring is still retained in the product as the evidence for this

mechanism.[97] Although many studies regarding this process have been achieved, studying the

behavior of palladium on the variety of substrates is still compelling for insightful

understanding.

Scheme 4.1: Pathways of 6-endo-trig and 5-exo-trig cyclizations


65

Recently, the utility of easily accessible N-tosylhydrazones as the coupling partner for

metal-catalyzed cross-coupling reactions has attracted growing attention.[28–31,98] As discussed

earlier in chapter 1, the method relies on the insertion of carbene species, generated in situ from

N-tosylhydrazones, to Pd(II) complexes. In 2007, the group of Barluenga developed

palladium-catalyzed cross coupling reactions of N-tosylhydrazones and aryl halides, efficiently

affording polysubstituted olefins.[30] Furthermore, the presence of the double bond in obtained

olefins attracts a sequential intramolecular Heck cyclization. To exemplify, Valdes et. al.

reported a palladium-catalyzed autotandem process which involves cross-coupling of

N-tosylhydrazones with 2,2′-dibromobiphenyls followed by a 5-exo-trig Heck-type cyclization,

final β-hydride elimination step to give the formation of various polycyclic compounds

(Scheme 4.2a).[99]

Scheme 4.2: Pd-catalyzed cyclization of dibrominated compounds with hydrazones

From this perspective, I wish to report a novel tandem process started from the

cross-coupling reaction of N-tosylhydrazones with dibromide compounds, then followed by a

sequence of intramolecular 5-exo-trig, 3-exo-trig cyclization, ring opening, β-hydride

elimination in the presence of a single palladium catalyst to give 6-endo-trig cyclization

products (scheme 4.2b). The obtained fused heterocycles, heterotetracenes and


66

heteropentacene, with large π-extended conjugated aromatic system are important in both

materials science and medicinal chemistry.[100] To the best of my knowledge, only few tandem

procedures to access these fused systems were developed to date.[101]

4.2. Synthesis of naphtho-fused heterocycles

For the initial investigation, 3-bromo-2-(2’-chlorophenyl)benzo[b]thiophene (4.1a) and

acetophenone N-tosylhydrazone (4.2a) were chosen as model substrates (Scheme 4.3). Firstly,

I utilized Pd2(dba)3 and XPhos as the catalytic system and LiOtBu as the base, which are known

as standard conditions for the cross-coupling reaction of N-tosylhydrazones and aryl halides.

Two similar reactions at 90 °C in dioxane as the solvent were performed under argon. One

reaction was stopped after 2 hours, and the intermediate as the product of the first coupling was

isolated. The structure of the intermediate 4.1i was confirmed by NMR and mass spectra as the

new terminal double bond was formed and the chlorine still remained in the molecule. The

remaining reaction was continued and the reaction temperature was raised to 100 ºC. After 4 h,

complete conversion of 4.1a and formation of only one product with 72% yield were observed.

Surprisingly, the product was proved to be regioisomer 4.3a by X-ray crystallographic analysis,

which is different from the 6-endo-trig cyclization 4.3a’.

Scheme 4.3: Tandem reaction of 3-bromo-2-(2’-chlorophenyl)benzo[b]thiophene 4.1a with

N-tosylhydrazone of acetophenone 4.2a

Conditions: 4.1a (0.2 mmol, 1 equiv.), 4.2a (0.3 mmol, 1.5 equiv.), Pd2(dba)3 2.5 mol%,

XPhos 10 mol%, LiOtBu (0.8 mmol, 4 equiv.), dioxane (4 mL).


67

On the basis of these experimental results in the combination with reported literature on

domino palladium-catalyzed processes as well as Barluenga’s and Valdes’ reports of

N-tosylhydrazones and aryl halides, I postulate that the mechanism of the reaction followed a

sequence of intramolecular 5-exo-trig, 3-exo-trig cyclization, ring opening, and finally

β-hydride elimination. The proposed mechanism is described in Scheme 4.4. The catalytic cycle

is believed to initiate by the first oxidative addition of C-Br bond of 4.1a with palladium catalyst

to form an active Pd-complex (I). This complex reacts with the carbene generated from

N-Tosylhydrazone 4.2a to give new palladium active species (III) via intermediate complex

(II). The reductive elimination of complex (III) regenerates palladium(0) species and an

intermediate (4.4), which was isolated. The second oxidative addition of intermediate (4.4) with

palladium catalyst results in formation of a new active palladium complex (IV). The

intramolecular cyclization of this palladium species (IV) via 5-exo-trig, 3-exo-trig cyclization,

and then ring opening of cyclopropane lead to the more stable palladium complex (VII). A

second reductive elimination of palladium complex (VII) releases the cyclized product (4.3a)

and H[Pd]Cl, which reacts with base to reproduce palladium(0) catalyst (Schem 4.4).


68

Scheme 4.4: Proposed mechanism of Pd-catalyzed cyclization of dibrominated compounds

with hydrazones.


69

Scheme 4.5: Tandem reaction of 2,2′-dibromobiphenyl 4.1b and

3-bromo-2-(2-bromophenyl)pyridine 4.1c.

Reaction conditions: 1 (0.2 mmol), 4.2a (0.3 mmol, 1.5 equiv.), Pd2(dba)3 2.5 mol%, XPhos

10 mol%, LiOtBu (0.8 mmol, 4 equiv.), dioxane 4 mL, 110 °C 24 h.* inseparable mixture

In addition, the reaction 2,2′-dibromobiphenyl (4.1b) and N-tosylhydrazone of

4’-methylacetophenone (4.2b) was carried out under the same conditions (Scheme 4.5). It is

worth to mention again that the tandem reaction of 2,2′-dibromobiphenyl and N-tosylhydrazone

of cyclic ketones underwent β-hydride elimination after the 5-exo-trig cyclization to afford

5-membered ring spiro compounds. In this work, the absence of β-hydrogens promoted

3-exo-trig cyclization to the double bond of benzothiophene which is not fully conjugated in

the aromatic system. However, in the case of 2,2′-dibromobiphenyl, the alkyl palladium

complex was not able to perform 3-exo-trig cyclization to the stable conjugated aromatic system

of benzene. Therefore, only the uncyclized product was detected after 24 h. The same result

was observed with 3-bromo-2-(2-bromophenyl)pyridine. These results also confirmed the

hypothesis about the mechanism of the reaction.

In order to improve the yield of the desired products, I utilized

3-bromo-2-(2-bromophenyl)benzo[b]thiophene (4.1d) as the starting material instead of

3-bromo-2-(2’-chlorophenyl)benzo[b]thiophene (4.1a). The reaction was performed under the

same conditions at 90 °C. Surprisingly, the reaction completed after 4 h producing only 4.3a

with 83% yield. Then, other combinations of Pd(OAc)2, Pd2(dba)3 and different ligands were

examined, however, no significant improvement of yield was observed. Therefore, the

combination of Pd2(dba)3 and XPhos proved to be the best so far. Increasing the amount of

Pd2(dba)3 to 5 mol% and XPhos to 20% increased the yield to 85%, so it was not reasonable to

use more amount of catalyst. As I reviewed the literature, almost of the publications related to


70

the cross-coupling of N-tosylhydrazones employed the conditions with LiOtBu as the base and

dioxane as the solvent, so the combination of LiOtBu and dioxane is believed to be important

for the first cross-coupling of N-tosylhydrazones. Moreover, the reaction was additionally

carried out in toluene but resulted in a complicated mixture, without the possibility to isolate

the pure compound. The reaction was also tested at 60 °C, 90 °C, and 110 °C. At 60 °C, after

4h, I detected mainly the intermediates. At 110 °C, the reaction completed after 2 hours, but

more spots on the TLC were observed, one of them overlapped with the spot of the product,

leading to the difficulty in isolating the pure product, so I found that carrying out the reaction

at 90 °C was most suitable for this purpose. Interestingly, the formation of two intermediates

was observed in this case, because the first coupling of N-tosylhydrazone with 4.1d could

undergo at either C-Br bond (Scheme 4.6). The two intermediates gave the same palladium

complex after the 5-exo-trig cyclization (similar to complex V), thus, only one product was

formed. Besides, double Heck reaction of 4.1d with styrene utilizing above conditions as well

as conditions reported by Blacklock et. al. produced a complicated mixture without the

formation of 4.3a.[102] Therefore, the cross-coupling reaction of N-tosylhydrazone was proved

to be superior in this tandem reaction.

Scheme 4.6: Tandem reaction of 3-bromo-2-(2-bromophenyl)benzo[b]thiophene 4.1d and

N-tosylhydrazones.

Encouraged by these results, I examined the scope and limitation of the tandem reaction

by varying the substrates (table 4.1). Firstly, the tandem reactions of various N-tosylhydrazones

were performed with 3-bromo-2-(2’-bromophenyl)benzo[b]thiophene 4.1d. To my delight, the

optimized conditions were applicable for numerous N-tosylhydrazones of substituted

acetophenones. Both electron-donating and electron-withdrawing groups on N-tosylhydrozones

resulted in only one isomer from good to excellent yields. N-tosylhydrazone of

4’-methoxyacetophenone gave the best yield of 95% (4.3i) while the trifluoromethyl substituent


71

on acetophenone gave the poorest yield with 53% (4.3c). There is no predictable effect of

substituents on acetophenones moiety on yields of the reaction. The reaction conditions are

tolerable with several substituents such as unprotected hydroxyl (4.3d) or cyano groups (4.3e).

N-tosylhydrazone derived from hetero-aromatic acetophenone such as 4-acetylpyridine also

gave the desired product under the reaction conditions (4.3h). Interestingly, a heteropentacene

(4.3o) could be successfully prepared with 34% yield in the employment of reaction conditions

with corresponding 3,3'-dibromo-2,2'-bibenzo[b]thiophene. Unfortunately, the reaction of

N-tosylhydrazone of 1,2-diphenylethan-1-one with 4.1d resulted in an inseparable mixture.

Table 4.1: Synthesis of benzo[b]naphtho[2,1-d]thiophenes

Compound Ar Structure Yield (%)

4.3b

90

4.3c

53

4.3d

81

4.3e

68


72

4.3f

89

4.3g

75

4.3h

56

4.3i

95

4.3j

80

4.3k

71

4.3l

65


73

4.3m

67

4.3n

63

4.3o

34*

4.3p

0**

Conditions: 4.1d (0.2 mmol), 4.2 (0.3 mmol, 1.5 equiv.), Pd2(dba)3 2.5 mol%, XPhos

10 mol%, LiOtBu (0.8 mmol, 4 equiv.), dioxane 4 mL, 90 °C, 4 h. *) 3,3'-dibromo-2,2'-bibenzo[b]thiophene was used instead of 4.1d. **) 3-bromo-2-(2-bromophenyl)thiophene was used instead of 4.1d, a mixture of uncyclized

intermediates was obtained instead of 4.3p.

Figure 4.1: The structure of 4.3a determined by X-ray crystallographic analysis


74

Figure 4.2: The structure of 4.3b determined by X-ray crystallographic analysis

In order to further explore the scope of reaction, I studied the reaction with other dibromide

derivatives from different heterocycles. The reaction gave good yields and regioselectivity

when applied for 3-bromo-2-(2-bromophenyl)benzofuran 4.1e. The reaction was assumed

following the proposed mechanism for 3-bromo-2-(2’-bromophenyl)benzo[b]thiophene,

forming similar isomer (table 4.2). Higher temperature and longer reaction time were required

when 3-bromo-2-(2-bromophenyl)-1-methyl-1H-indole 4.1f was employed as the precursor,

producing benzo[a]carbazole derivatives in relatively lower yields (table 4.3).

Table 4.2: Synthesis of naphtho[1,2-b]benzofurans

Compound Ar Structure Yield (%)

4.5a

60


75

4.5b

45

4.5c

77

4.5d

41

Reaction conditions: 4.1e (0.2 mmol), 4.2 (0.3 mmol, 1.5 equiv.), Pd2(dba)3 2.5 mol%,

XPhos 10 mol%, LiOtBu (0.8 mmol, 4 equiv.), dioxane 4 mL, 90 °C, 4 h.

Table 4.3: Synthesis of benzo[a]carbazoles

Compounds Ar Structure Yield

4.6a

31


76

4.6b

45

4.6c

39

Reaction conditions: 4.1f (0.2 mmol), 4.2 (0.3 mmol, 1.5 equiv.), Pd2(dba)3 2.5 mol%,

XPhos 10 mol%, LiOtBu (0.8 mmol, 4 equiv.), dioxane 4 mL, 100 °C, 12 h.

4.3. Conclusion

In conclusion, I have developed a tandem reaction for regioselective synthesis of a range

of π-extended polyheterocyclic aromatic compounds. The reaction can be applied to numerous

substrates with the tolerance of various functional groups. Products of the reaction,

heterotetracenes and a heteropentacene, are interesting targets to explore potential applications

in materials science as well as medicinal chemistry. This strategy could be applied in the

synthesis of advanced functional materials containing larger π-extended heteroacene

compounds.


T. N. Ngo, T. T. Dang, A. Villinger, P. Langer, Adv. Synth. Catal. 2016, 358, 1328–1336.

Cyclization of Hydrazone Dianions

77

5. Efficient one-pot synthesis of 5-perfluoroalkylpyrazoles by

cyclization of hydrazone dianions

5.1. Introduction

Dianions, contained two negative charges, are known for versatility in cyclization reactions

with dielectrophiles to form rings with various size. The group of Prof. Langer has developed

several domino or one-pot cyclization reactions based on 1,1-, 1,2-, 1,3-, and 1,4-dianions,

affording important core structures ranging from three- to six-membered rings. These concepts

can apply to synthesize heterocycles, for example, the regioselective synthesis of functionalized

pyrroles by one-pot cyclocondensation of 1,3-dicarbonyl dianions with α-azidoketones. Due to

dianions are highly reactive, reactions with dielectrophiles can result in elimination,

polymerization, decomposition, and formation of open chained products. An important

discovery to overcome the drawback of dianions is the employment of electroneutral dianions,

or masked dianions, which are activated when reacting with Lewis acid. The idea was well

demonstrated by using 1,3-bis-silyl enol ethers as masked dianions in cyclization reactions with

dielectrophiles.[103]

Scheme 5.1: One-pot cyclocondensation of 1,3-dicarbonyl dianions with α-azidoketones

Fluorinated organic compounds have become essential in the development of

agrochemicals, and more importantly, in pharmaceuticals.[104] Recently, the number of

approved drugs or drug candidates containing fluorine is increasing noticeably, contributing

about 25% compounds in pharmaceuticals. In fact, three of ten best-selling drugs contain at

least one fluorine: rosuvastatin used for the treatment of high cholesterol and prevent

cardiovascular disease,[105] sofosbuvir, and ledipasvir used for the treatment of hepatitis C

infection.[106] The high electronegativity combining with its small size makes fluorine


78

extremely low polarizability, resulting in drastic changes in physicochemical properties of

fluoroorganic compounds, most importantly enhancing thermal stability and lipophilicity, thus,

increasing bioavailability. In addition, fluorine has the size similar to hydrogen, however, could

act as a hydrogen bond acceptor, benefiting the molecules with similar geometry to those of

hydrogen but completely different interactions.[107]

Moreover, nitrogen-containing heterocycles constitute a large part of biologically active

compounds. Among them, pyrazole moiety is widely recognized, presenting in many leading

drugs,[108] such as Zometapine[109] and Viagra[110] and in agrochemicals, such as Tolfenpyrad

and Fenpyroximate.[111] Recently, the progression of synthetic fluorination methods leads to the

discovery of a pyramid of fluorinated pyrazoles with remarkable biological activities.[112] For

example, many important drugs and agrochemicals, such as Celecoxib (antiarthritic),[113]

Mavacoxib (antiarthritic),[114] Razaxaban (anticoagulant),[115] Fluazolate (herbicide),[116]

Penthiopyrad (fungicide)[117] are derived from trifluoromethylated and perfluoroalkylated

pyrazoles. Therefore, developing new efficient methods for the synthesis of fluorinated

heterocycles, particularly fluorinated pyrazoles, is still in demand.

Figure 5.1: Drugs and agrochemicals containing trifluoromethylated pyrazoles

There are two strategies to introduce florine to a structrue: direct fluorination or synthesis from

pre-fluorinated building blocks. Although direct fluorination is flourishing and gaining

significance with the rapid development of transition metal-catalyzed reactions, the strategy


79

involving fluorine-containing intermediates is still efficient in various scenarios. Based on

developed synthetic methods for specific class of heterocycles, which are already proved their

efficiency, fluorine or fluorinated groups, such as trifluoromethyl or perfluoroalkyl, are

embedded in molecules of the precursors.

Particularly, conventional methods for the synthesis of pyrazoles are based on the

cyclocondensation of hydrazine with 1,3-dielectrophiles, such as 1,3-dicarbonyl or

α,β-unsaturated carbonyl compounds.[118] Another approach is 1,3-dipolar cycloadditions of an

alkyne with various 1,3-dipoles, such as diazoalkanes, nitrilimines, or azomethine imines.[119]

Scheme 5.2: Synthesis of pyrazoles

Trifluoromethylated pyrazoles have been prepared by cyclocondensation of

trifluoromethyl-1,3-diketones with phenylhydrazine, however, mixtures of regioisomers were

formed.[120] In order to discover more efficient approaches for the synthesis of

trifluoromethylated pyrazoles, several research groups have focused on the development of new

methods to address the issue of regioselectivity. Frizzo et al. reported a useful method for the

synthesis of 5-trifluoromethylpyrazoles based on the condensation of

4-alkoxy-1,1,1-trifluoro-3-alken-2-ones with phenyl-hydrazine using the ionic liquid

[BMIM][BF4] as the solvent. In general, this method gave very good yields of

5-trifluoromethylpyrazoles, but for some derivatives, regioisomeric mixtures were still

obtained.[121] Recently, some useful methods have been developed to overcome this problem,

e.g., the use of fluorinated alcohols (TFE and HFIP) in the cyclocondensation of

trifluoromethyl-1,3-diketones with phenylhydrazine or the employment of

4-trifluoromethyl-sydnones as starting materials in the cycloaddition reaction with alkynes.[122]

In early 2014, Mykhailiuk and coworkers reported an interesting approach to the synthesis of


80

3-trifluoromethylpyrazoles in very good yields based on the [3+2] cycloaddition of CF3CHN2

with alkynes.[123] Very recently, a new method for the synthesis of 3-trifluoromethylpyrazoles

was described via trifluoromethylation/cyclization of α,β-alkynic hydrazone with hypervalent

iodine reagent.[124]

In addition, another interesting approach is the cyclization of hydrazone dianions with

esters. Hauser and co-workers were the first to report the synthesis of 5-substituted pyrazoles

by cyclization of hydrazone 1,4-dianions with esters. The same strategy was applied by the

group of Prof. Langer to prepare pyrazole-5-carboxylates and pyrazole-1,5-dicarboxylates.[125]

I believe that this method could be employed to prepare regioselectively

5-perfluoroalkylpyrazoles (scheme 5.3).

Scheme 5.3: Synthesis of pyrazoles by cyclization of hydrazone 1,4-dianions

In this chapter, a convenient and efficient method for the synthesis 5-trifluoromethyl- and

5-perfluoroalkylpyrazoles by one-pot cyclization of hydrazone 1,4-dianions with fluorinated

esters is being described. In addition, the activity of the pyrazoles prepared as inhibitors of

human tissue-nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline

phosphatase (h-IAP) are being discussed. Furthermore, the effects of these molecules were also

tested on two other human ectonucleotidases, ecto-nucleotide pyrophosphatase/

phosphodiesterase-1 (h-NPP1) and h-NPP3.

5.2. Synthesis of perfluoroalkylated pyrazoles

Hydrazones 5.2 were prepared by condensation of ketones 5.1 with hydrazine derivatives.

This reaction proceeded under solvent free (‘green’) conditions at room temperature and is

catalyzed by acetic acid and provided nearly quantitative yields of hydrazones. Then, 5.2 were

converted to their dianions by treatment with 2 equivalents of n-BuLi in THF at -78 °C.

Subsequently, ethyl perfluorocarboxylates 5.3 were added to the reaction mixture. After

warming to ambient temperature, either trifluoroacetic acid (TFA) or p-toluenesulfonic acid


81

(PTSA) was added to the reaction mixture to give perfluoroalkylated pyrazoles 5.4 or 5.5,

respectively (Scheme 5.4 & table 5.1). The formation of the product proceeds by the attack of

the carbon of dianion A onto 5.3 to give intermediate B, cyclization by the attack of the nitrogen

atom onto the carbonyl group to give intermediate C, and subsequent acid-mediated

dehydration. Treatment of intermediate C with TFA under reflux in dioxane allowed

5-perfluoromethylated pyrazoles 5.4 in good to excellent isolated yields. On the other hand,

treatment of intermediate C with PTSA (reflux, toluene) gave the N-deprotected

3-perfluoromethylpyrazoles 5.5. This could be explained by the fact that PTSA is a stronger

acid than TFA. The carbamate protecting group was removed when PTSA was used but

remained intact when TFA was used. It is noteworthy that the synthesis of compound 5.4f could

be scaled up to gram quantities. Starting with 10 mmol of 5.1f, product 5.4f was isolated in

88% yield (2.67 g).

Scheme 5.4: Synthesis of pyrazoles 5.4 and 5.5

Conditions: i, neat, acetic acid (catalytic amount, 3 drops), 20 °C; ii, 1) 2.2 equiv. n-BuLi,

THF, -78 °C to 20 °C. 2) 1.5 equiv. 5.3a, -78 °C to 20 °C. 3) TFA, reflux 2h (or PTSA,

reflux, 8h).


82

Table 5.1: Synthesis of pyrazoles 5.4 and 5.5

Compound Ar R RF Structure Yield (%)

5.4a

CF3

89

5.4b

CF3

79

5.4c

CF3

81

5.4d

CF3

61

5.4e

CF3

74

5.4f

CF3

87

5.4g

CF3

90

5.4h

CF3

82

5.4i

CF3

78

5.4j

CF3

64


83

5.4k

C2F5

95

5.4l

C2F5

91

5.4m

C2F5

93

5.4n

C2F5

85

5.4o

C3F7

83

5.4p

C3F7

76

5.4q

CO2Et CF3

57

5.4r

CO2Et CF3

65

5.5a

H CF3

51

5.5b

H C2F5

56

5.5c

H C3F7

57


84

5.5d

H CF3

78

5.5e

H C2F5

86

5.5f

H C3F7

64

5.5g

H CF3

75

5.5h

H C2F5

74

5.5i

H C3F7

67

The cyclization of the dianion of the hydrazone of cyclododecanone 5.2s with ethyl

2,2,2-trifluoroacetate afforded the annulated trifluoromethylated pyrazole 5.4s in 80% yield

(Scheme 5.5). The cyclizations of the hydrazones of cyclohexanone 5.2t, cyclohex-2-en-1-one

5.2u and tetralone 5.2v afforded the corresponding products 5.4t-v.


85

Scheme 5.5: Synthesis of 5.4s-v

Conditions:i, neat, acetic acid (catalytic amount, 3 drops), 20 °C; ii, 1) 2.2 equiv. n-BuLi,

THF, -78 °C to 20 °C. 2) 1.5 equiv. 5.3a, -78 °C to 20 °C. 3) TFA, reflux 2h.

Recently, it has been reported that trifluoromethylated indazole D32 represents a highly

selective ligand for the estrogen receptor β. Trifluoromethylated indazole E33 is a useful agent

for the treatment of obesity and diabetes (Figure 5.2). Therefore, it would be interesting to

prepare trifluoromethylated indazoles starting from ring-fused pyrazoles.

Figure 5.2: Bioactive trifluoromethylated indazoles D and E

The dehydrogenation of pyrazoles 5.4s and 5.4t with DDQ afforded the desired indazoles

5.6a and 5.6b in high yields, respectively. These experiments show that this methodology can

be successfully applied also for the synthesis of trifluorinated indazoles (scheme 5.6).


86

Scheme 5.6: Synthesis of 5.6a and 5.6b

Conditions:i, 2.0 equiv. DDQ, toluene, reflux, 3 h.

The cyclization of the dianions of oximes 5.7a, b with ethyl trifluoroacetate and subsequent

treatment with TFA (reflux, 8h) afforded 5-trifluoromethylated isoxazoles 5.8a and 5.8b in 57%

and 62% isolated yields, respectively.

Scheme 5.7: Synthesis of isoxazoles 5.8a, b

Conditions:i, 1) 2.2 equiv. n-BuLi, THF, -78 °C to 20 °C. 2) 1.5 equiv. CF3COOEt, -78 °C to

20 °C. 3) TFA, reflux 2h.

5.3. Alkaline phosphatase and nucleotide pyrophosphatase activity and SAR

Intestinal alkaline phosphatase (IAP) is believed to play an important role in detoxification

of bacterial endotoxin, dephosphorylation of triphosphorylated and diphosphorylated

nucleotides, regulation of the intestinal microbiome, and regulation of intestinal lipid

absorption.[126] However, overexpression of IAP might have a connection with some

inflammatory bowel diseases such as Crohn’s disease.[127] On the other hand, tissue


87

non-specific alkaline phosphatases (TNAP), which participate in the maintenance of the PPi

level in the body, share significant homology with IAP.[128] Therefore, selective inhibitors

against IAP would be potential therapeutic agents. Interestingly, pyrazole derivatives were

observed having inhibitory activity against alkaline phosphatases.[129] In this context,

embedding fluorine atoms in pyrazole molecules is promising to the discovery of potential

inhibitors for APs. In addition, nucleotide pyrophosphatase/phosphodiesterases (NPPs), which

affect a number of processes like bone mineralization, cell proliferation, motility, and digestion,

are also important therapeutic targets and it is worth to examine the inhibitory activity of

fluorinated pyrazoles against them.[130]

All the fluorinated pyrazole derivatives were tested for human recombinant APs and NPPs

and they were found to be selective inhibitors of APs in comparison to NPPs. Against h-NPP1

and h-NPP3, these compounds exhibited low response of inhibition. The data obtained showed

that all the values were below 50%. Compound 5.4i was found to be the potent inhibitor of

h-TNAP having IC50 value of IC50 ±SEM = 0.45±0.01 µM. It can be suggested that the activity

of this compound might be due to the presence of a phenyl and a trifluoromethyl group at the

parent pyrazole ring. When the activity of this compound was compared with the other

derivatives containing naphthalene ring attached to parent pyrazole it was clearly observed that

compound having phenyl and side chain with less carbon atom, has more impact on activity

against h-TNAP. When the number of carbon and fluorine increased the activity of the

compound was decreased as it was reflected in activity values of 5.4m, 5.5d, 5.5e, and 5.5f.

Levamisole was used as a standard inhibitor against h-TNAP. Other compounds inhibited

h-TNAP with IC50 values in the range of IC50 ±SEM = 0.449±0.001 to 50.3±3.28 µM.

Compound 5.4n exhibited the most potent inhibition of h-IAP with an IC50value of IC50 ±SEM=

0.65±0.04 µM [sic] which is over 120 folds more efficient than the known standard inhibitor

L-phenylalanine. The comprehensive study of the compound structure was justified by

comparing with L-phenylalanine (known reference standard) which contain only one phenyl

ring. This confirmed that the presence of biphenyl group on the pyrazole ring might be

responsible for its high activity against h-IAP. On the other hand, when this compound was

compared with 5.4e containing biphenyl ring with the different carbon side chain it was

observed that with a reduced number of carbon atoms in the side chain, the activity of

compound was decreased against h-IAP. Other pyrazole derivatives displayed h-IAP inhibition

activity in the range IC50 ±SEM = 0.647±0.04 to 7.36±0.25 µM. The above-mentioned data

showed that most pyrazole derivatives were better inhibitors of h-IAP than of h-TNAP.


88

Table 5.2: Alkaline phosphatase AP (h-TNAP & h-IAP) and NPP (h-NPP1 & h-NPP3)

inhibition in presence of the synthesized compounds

5.4. Conclusion

In conclusion, I have demonstrated that a series of 5-trifluoromethylated and

5-perfluoroalkylated pyrazoles, including deprotected derivatives, could be efficiently and

selectively synthesized by one-pot cyclization of hydrazone dianions with ethyl

perfluorocarboxylates. In addition, two trifluoromethylated indazoles were prepared from the

corresponding bicyclic hydrazones. The cyclization of oxime dianions afforded

No.

h-TNAP h-IAP h-NPP1 h-NPP3

IC50 a

(µM)±SEM

IC50

a(µM)±SEM (%inhibition)b (%inhibition)b

5.4a 9.52±1.53 1.49±0.38 18.9% 12.5%

5.4b 11.1±1.06 1.22±0.22 23.4% 27.6%

5.4c 10.46±.65 1.63±0.41 21.2% 22.6%

5.4d 26.6±2.56 2.31±0.13 1.65% 4.87%

5.4e 3.23±0.48 1.41±0.05 12.4% 13.5%

5.4f 1.48±0.72 3.52±0.98 7.98% 19.8%

5.4g 2.59±0.38 5.78±0.74 13.8% 6.87%

5.4h 10.1±1.72 1.62±0.23 4.89% 2.76%

5.4i 0.45±0.01 4.46±0.78 23.2% 2.87%

5.4j 3.11±0.84 2.37±0.79 6.98% 1.09%

5.4k 2.11±0.28 5.12±0.84 34.5% 24.8%

5.4l 5.01±0.79 3.71±0.37 2.89% 4.67%

5.4m 1.35±0.06 2.19±0.05 38.4% 14.6%

5.4n

48.6±3.22 0.65±0.04 6.98% 9.87%

5.4o 50.3±3.28 1.35±0.14 28.2% 12.7%

5.4p 25.9±1.38 7.11±0.98 11.5% 17.8%

5.5a 11.6±1.28 7.36±0.25 3.08% 6.08%

5.5b 13.1±0.63 10.5±1.02 14.8% 18.9%

5.5c 4.34±0.03 2.91±0.35 39.1% 34.6%

5.5d 8.09±1.28 1.95±0.26 22.4% 18.7%

5.5e 13.9±1.08 4.47±0.97 6.87% 7.98%

5.5f 12.9±1.38 2.23±0.32 15.9% 10.8%

5.5g 1.62±0.11 2.39±0.36 19.3% 14.7%

5.5h 47.1±3.11 2.57±0.77 25.6% 29.8%

5.5i 2.04±0.17 1.96±0.33 28.2% 31.2%

5.6b 21.2±1.78 6.03±0.75 27.6% 12.6%

5.6a 17.2±0.89 5.84±0.37 12.8% 16.7%

Levamisole 19.21±0.001

L-Phenylalanine ------- 80.21±0.001

Values are expressed as mean ± SEM of n = 3. aThe IC50 is the concentration at which 50%

of the enzyme activity is inhibited. bThe % inhibition of the enzyme activity caused by 0.1

mM of the tested compound.


89

trifluoromethyl-substituted isoxazoles. All the compounds were selective inhibitors of APs with

little effect on h-NPP1 and h-NPP3. In addition, the data showed that most of the compounds

presented here inhibited h-IAP more efficiently than h-TNAP. Therefore these compounds

appear as selective inhibitors of h-IAP.The results reported herein are of considerable interest

for further applications in medicinal chemistry.


T. N. Ngo, S. A. Ejaz, T. Q. Hung, T. T. Dang, J. Iqbal, J. Lecka, J. Sevigny, P. Langer, Org.

Biomol. Chem. 2015, 13, 8277-8290.

APPENDIX

i

APPENDIX

Methods for compound characterization and analysis

Melting Points

Micro heating table HMK 67/1825 Kuestner (Büchi apparatus); Melting points are

uncorrected.

Nuclear Magnetic Reasonance Spectroscopy (NMR)

Bruker: AM 250, (62.9 MHz); Bruker: ARX 300, (75.4 MHz), Bruker: ARX 500,

(125 MHz). The chemical shifts are given in parts per million (ppm). Coupling constants are

given in Hz.

References for 1H NMR: TMS (δ = 0.00) or residual deuterated solvent (CDCl3 (δ = 7.26),

C6D6 (δ = 7.16), (CD3)2CO (δ = 2.05), (CD3)2SO (δ = 2.50)), for 13C NMR TMS (δ = 0.00) or

residual deuterated solvent (CDCl3 (δ = 77.16), C6D6 (δ = 128.06), (CD3)2CO (δ = 29.84;

206.26), (CD3)2SO (δ = 39.52)) were taken as internal standard. The splitting pattern was

characterized by s: singlet, d: doublet, t: triplet, q: quartet, quin: quintet, sex: sextet, m:

multiplet. More complicate coupling peaks are represented by combinations of the respective

symbol. For example, dt indicate to doublet of triplet. Distortionless enhancement polarization

transfer (DEPT) spectra were taken to determine the types of carbon signals.

Mass Spectroscopy (MS)

AMD MS40, Varian MAT CH 7, MAT 731 (EI, 70 eV), Intecta AMD 402 (EI, 70 eV, and

CI).

High Resolution Mass Spectroscopy (HRMS)

Finnigan MAT 95 or Varian MAT 311; Bruker FT CIR, AMD 402 (AMD Intectra).

Infrared Spectroscopy (IR)

Bruker IFS 66 (FT IR), Nicolet 205 FT IR; Nicolet Protege 460, Nicolet 360 Smart Orbit

(ATR); KBr, KAP, Nujol, and ATR; Peaks were characterized with abbreviation: w = weak,

m = medium, s = strong, br = broad.

APPENDIX

ii

X-ray Crystal Structure Analysis

Bruker X8Apex diffractometer with CCD camera (Mo Kαradiation and graphite

monochromator, λ=0.71073 Å). The structures were solved by direct methods andrefined by

full-matrix least-squares procedures on F2 with the SHELXTL software package.

UV/Vis spectroscopy

Lambda 5 (Perkin Elmer) and Analytic Jena Specord 50 UV/VIS spectrometer in

acetonitril.

Fluorescence spectroscopy

Fluoromax4P-0759D-0311-FM. The samples were dissolved in dichloromethane. The

quinine hemisulfate salt monohydrate in 0.05M H2SO4 which has a fluorescence yield of 0.52,

was used as the standard for the fluorescent quantum yield determination.

Thin Layer Chromatography (TLC)

Merck Silica 60 F254 on aluminum foil from Macherey-Nagel. Detection under UV light

at 254 nm and/or 365 nm of wavelength and visualize by dipping in TLC stains solution

including conc. H2SO4/vaniline, Cerium-ammonium-molybdate (CAM), ceric sulfate and

Dragendorff reagent.

Column chromatography

Column chromatography was performed over Merck silica gel (63-200 µM) as normal

column and (40-63 µM) as flash column. All the solvent were distilled prior to use.

Biological protocols

The biotests were performed by Sundas Sarwar, Syeda Abida Ejaz, and Syeda Mahwish

Bakht in the group of Dr. Jamshed Iqbal, Centre for Advanced Drug Research, COMSATS

Institute of Information Technology, Abbottabad, Pakistan.

Cell Transfection with Human APs and NPPs

COS-7 cells were transfected with plasmids expressing human APs (TNAP & IAP) or

human NPPs ((NPP-1) or (NPP-3)) in 10-cm plates, by using Lipofectamine. The confluent

cells were incubated for 5 h at 37 °C in DMEM/F-12 in the absence of fetal bovine serum and

APPENDIX

iii

with 6 µg of plasmid DNA and 24 µL of Lipofectamine reagent. The same volume of

DMEM/F-12 containing 20% FBS was added to stop the transfection and cells were harvested

48–72 h later.

Preparation of membrane fractions

The transfected cells were washed three times at 4 °C, with Tris–saline buffer, collected by

scraping in the harvesting buffer (95 mM NaCl, 0.1 mM PMSF, and 45 mM Tris buffer, pH

7.5) and washed twice by centrifugation at 300×g for 5 min at 4 °C. Subsequently, cells were

resuspended in the harvesting buffer containing 10 µg/mL aprotinin and sonicated. Nuclear and

cellular debris were discarded by 10 min centrifugation (300×g at 4 °C). Glycerol was added to

the resulting supernatant at a final concentration of 7.5%.

Samples were kept at -80 °C until used. Protein concentration was estimated using Bradford

microplate assay and bovine serum albumin was used as a standard.

Protocol of Cholinesterase inhibition assay

For the determination of cholinesterase inhibition, electric eel and horse serum were used

as sources of AChE and BChE, respectively. AChE and BChE inhibition was measured in vitro

by the Ellman’s spectrophotometric method with slight modification. The reaction started by

mixing 20 µL assay buffer, 10 µL of test compound and 10 µL of enzymes (0.5 and 3.4 U/mg

of AChE or BChE, respectively). Then the reaction mixture was incubated for 10 min at 25 °C.

At the end of the pre/incubation period, 10 µL of 1 mM acetylthiocholine iodide or

butyrylthiocholine chloride were added to the respective AChE or BChE enzyme solution and

50 µL of 0.5 mM, 5,5’/Dithiobis/2/Nitrobenzoic Acid (DTNB) was added as coloring reagent.

The mixtures were incubated for 15 min at 25 °C. The formation of enzymatic product was

determined by the variation in absorbance measured at 405 nm with a microplate reader

(Bio/Tek ELx800TM, Instruments Inc., Winooski, VT, USA). In this bioactivity assay, the

standard drugs, neostigmine and donepezil were used. The buffer for enzyme dilution

comprised of 50 mM Tris/HCl containing 0.1% (w/v) BSA (pH 8). To remove the effect of

DMSO on enzymes, a blank assay was performed without any enzyme and accounted as

non/enzymatic reaction. The analysis of each concentration was done in triplicate and the IC50

values were calculated with the linear regression parameters. The computer program used for

this purpose is GraphPad Prism 5.0 (San Diego, CA, USA).

Protocol of Monoamine oxidase inhibition assay

APPENDIX

iv

Monoamine oxidase inhibitory activities of the synthesized compounds were evaluated

using standard protocol. Assays were performed in 200 µL final volume in 96 well plate. Rat

liver mitochondria were pretreated for 15 min at room temperature with an aqueous solution of

clorgyline (30 nM) or deprenyl (300 nM) to irreversibly block MAO/A or MAO/B activity,

respectively. Test compounds (2 µL), dissolved in DMSO (100%), were added to 90 µL of

mitochondrial preparation (25.0 µg of protein for rat MAO/A and 5.0 µg protein for rat MAO/B)

and were incubated for 30 min prior to the addition of 90 µL of freshly prepared Amplex Red

fluorogenic substrate. The Amplex Red reagent were used as follows, for a 96 well plate, 1.0 mg

of Amplex Red, dissolved in 200 µL of DMSO (100%) and 100 µL of reconstituted horseradish

peroxidase (HRP 200 U/mL) stock solution (kit vial + 1.0 mL of 50 mM sodium phosphate

buffer) was added to 9700 µL of sodium phosphate buffer (250 mM, pH 7.4). The enzymatic

reaction was started by the addition of 20 µL/well of an aqueous solution of the substrate p/

tyramine (300 µM final concentration). Deprenyl and clorgyline (each in a final concentration

of 1.0 µM) were used to determine non MAO/B and non/MAO/A enzyme activity, respectively.

Fluorescence measurements were performed over 45 min and the concentration response curves

of clorgyline and deprenyl served as positive controls for the rat MAO/A and rat MAO/B assay,

respectively.

Protocol of Alkaline Phosphatase Assay (h-TNAP & h-IAP)

A chemiluminescent substrate, CDP-star, was used for the determination of activity of

h-TNAP and h-IAP. The conditions for the assay were optimized with the slight modifications

in the previously used spectrophotometric method. The assay buffer was composed of 2.5 mM

MgCl2, 0.05 mM ZnCl2 and 8 M DEA (pH 9.8). Initial screening was performed at a

concentration of 0.2 mM of the tested compounds. The total volume of 50 µL contained 10 µL

of tested compound (0.2 mM with final DMSO 1% (v/v)), 20 µL of h-TNAP (46 ng of protein

from COS cell lysate in assay buffer) or of h-IAP (57 ng protein in assay buffer). The mixture

was pre-incubated for 5-7 minutes at 37 °C and luminescence was measured as pre-read using

microplate reader (BioTek FLx800, Instruments, Inc. USA). Then, 20 µL of CDP-star (final

concentration of 110 µM) was added to initiate the reaction and the assay mixture was incubated

for 15 min more at 37 °C. The change in the luminescence was measured as after-read. The

activity of each compound was compared with total activity control (without any inhibitor).

Levamisole (2 mM per well) and L-phenylalanine (4 mM per well) were used as a positive

control for the inhibition of h-TNAP and h-IAP, respectively. For the compounds which

exhibited over 50% inhibition of either h-TNAP activity or h-IAP activity, full concentration

APPENDIX

v

inhibition curves were produced to evaluate IC50 values. For this purpose, 6 to 8 serial dilutions

of each compound were prepared in assay buffer and their dose response curves were obtained

by assaying each inhibitor concentration against both ALPs using the above mentioned reaction

conditions. All experiments were repeated three times in triplicate. The Cheng Prusoff equation

was used to calculate the IC50 values, determined by the non-linear curve fitting program

PRISM 5.0 (GraphPad, San Diego, California, USA).

Protocol of Nucleotide pyrophosphatase (h-NPP-1 & h-NPP-3) activity

The conditions for the assay were optimized with the slight modifications in the previously

used spectrophotometric method. The reaction was carried out in the assay buffer which

contained 5 mM MgCl2, 0.1 mM ZnCl2, 50% glycerol and 50 mM tris-hydrochloride (pH: 9.5).

Initial screening was performed at a concentration of 0.1 mM of the tested compounds. The

total volume of 100 µL contained 70 µL of the assay buffer, 10 µL of tested compound (0.1 mM

with final DMSO 1% (v/v)) and 10 µL of h-NPP-1 (27 ng of protein from COS cell lysate in

assay buffer) or 10 µL of h-NPP-3 (25 mg of protein from COS cell lysate in assay buffer). The

mixture was pre-incubated for 10 minutes at 37 °C and absorbance was measured at 405 nm as

pre-read using microplate reader (BioTek FLx800, Instruments, Inc. USA). The reaction was

then initiated by the addition of 10 µL of p-Nph-5-TMP substrate at a final concentration of

0.5 mM and the reaction mixture was incubated for 30 more min at 37 °C. The change in the

absorbance was measured as after-read. The activity of each compound was compared with the

reaction in absence of synthesized compounds/inhibitors. The compounds which exhibited over

50% inhibition of either the h-NPP-1 activity or h-NPP-3 activity were further evaluated for

determination of IC50 values. For this purpose, their dose response curves were obtained by

assaying each inhibitor concentration against both NPPs using the above mentioned reaction

conditions. All experiments were repeated three times in triplicate. The Cheng Prusoff equation

was used to calculate the IC50 values, determined by the non-linear curve fitting program

PRISM 5.0 (GraphPad, San Diego, California, USA).

Preparation of receptor and ligands

Prior to docking procedures, the receptor crystalline structures were downloaded from

RCSB Protein Data Bank. As no good resolution template was present for eeAChE, the crystal

structure of Torpedo californica AChE (PDB ID 3I6Z) with resolution of 2.19 Å and Human

BuChE (PDB ID 1P0I) of human BuChE with resolution of 2.0 Å were downloaded. Receptors

for docking studies were prepared by using Load or Prepare Utility of LeadIT v2.1.8 from

APPENDIX

vi

BioSolveIT GmbH, Germany. The active site of the receptor was defined by selecting amino

acid residue in 7.5 Å radius around reference ligands i.e. Galantamine (G6X) in AChE receptor

and Butanoic acid (BUA) in BuChE.

Ligands: Chemical structures of the ligands were drawn using ACD/ChemSketch v14.1,

and 3D optimized. Using ANTECHAMBER, Gasteiger charges were added. Ligand structures

were then subjected to energy minimization using default values in Chimera v1.10.04 and saved

as mol2 files.

Molecular docking

Molecular docking was performed by Syed Jawad Ali Shah in the group of Dr. Jamshed

Iqbal, Centre for Advanced Drug Research, COMSATS Institute of Information Technology,

Abbottabad, Pakistan.

Molecular docking was carried out using FlexX utility of LeadIT v2.1.8 from BioSolveIT

GmbH, Germany. The binding site was defined as stated above. Water, amino acid residues and

small molecules were handled automatically by the software. Compounds were protonated as

in aqueous solution. Top ranking 30 poses were kept and further used for HYDE Assessment.

Hyde assessment and visual affinity

Top ranking docked poses were then subjected to HYDE assessment of LeadIT v.2.1.8 to

determine the Binding Free Energy (binding affinity). HYDE is based on two parameters. One

is hydrogen bonding and the second one is dehydration term i.e. ΔGiHYDE = Ʃ ΔGi

Dehydration + Ʃ

ΔGiH-bond

General procedure for the synthesis of pyrrolocoumarins

Compound 2.4 (0.3 mmol), aniline 2.5 (0.36 mmol, 1.2 equiv), Pd(OAc)2 (0.03 mmol,

10% mol), SPhos (0.06 mmol, 20% mol), CuI (20% mol), and Cs2CO3 (2.5 equiv. 0.9 mmol)

were placed in a dried pressure tube equipped with a septum. The reaction was back-filled with

argon three times. Then dry and degassed DMF (4 mL) was added under argon and the septum

was replaced with a Teflon cap. The reaction mixture was allowed to stir at 80 °C for 4 h. Then

the reaction mixture was cooled to room temperature and was filtered through a pad of Celite.

The Celite pad was washed three times with ethyl acetate (3x20 mL). The filtrate was dried

under reduced pressure, and the product 2.6 was obtained after flash chromatography on a silica

gel column.

APPENDIX

vii

3-(4-Methoxyphenyl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6a

White solid, 64% (70.5 mg). M.p.: 197–199 °C.

IR (ATR, cm-1): 3068.7 (w), 2971.0 (w), 2840.9 (w), 1720.8 (s),

1608.6 (m), 1512.0 (s), 1464.4 (s), 1356.6 (m), 1249.1 (m),

1168.0 (s), 1065.4 (s), 973.8 (s), 831.2 (m), 755.7 (s), 693.9 (s),

553.3 (s).

1H NMR (300 MHz, CDCl3) δ 7.89 – 7.79 (m, 1H, CHAr), 7.40 (dd, 3J = 4.9, 4J = 1.4 Hz, 2H,

CHAr), 7.34 – 7.15 (m, 8H, CHAr), 6.95 – 6.84 (m, 3H, CHAr), 3.83 (s, 3H, OCH3).

13C NMR (75 MHz, CDCl3) δ 159.5 (C-OCH3), 154.2 (C=O), 151.6, 145.5, 131.2, 130.5, 130.3

(CAr), 129.3 (2CHAr), 129.0 (2CHAr), 128.2 (3CHAr), 127.9, 123.8, 122.8 (CHAr), 118.3, 117.7

(CAr), 116.9 (CAr), 113.7 (2CHAr), 102.9 (CHAr), 55.3 (OCH3).

MS (EI,70 eV): m/z (%) = 367 (M+, 100), 278 (5), 205 (10), 176 (9), 133 (5), 77 (4).

HRMS (EI, 70 eV): calcd for C24H16O3N1 ([M]+): 367.12029, found: 367.11931.

3-(3-Methoxyphenyl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6b

Yellowish solid, 47% (51.7 mg). M.p.: 182–183 °C.

IR (ATR, cm-1): 3116.2 (w), 3063.7 (w), 2951.1 (w), 2849.3 (w),

1710.4 (s), 1598.8 (m), 1487.0 (m), 1463.4 (s), 1356.2 (m),

1213.5 (s), 1111.8 (m), 1031.5 (s), 989.4 (m), 954.4 (m), 850.0

(m), 762.4 (s), 693.9 (s), 647.1 (m).

1H NMR (300 MHz, CDCl3) δ 7.84 (d, 3J = 7.6 Hz, 1H, CHAr), 7.47 – 7.36 (m, 2H, CHAr),

7.36 – 7.17 (m, 7H, CHAr), 7.06 – 6.74 (m, 4H, CHAr), 3.74 (s, 3H, OCH3).

13C NMR (63 MHz, CDCl3) δ 159.7 (C-OCH3), 154.0 (C=O), 151.6, 145.3, 138.4, 131.1, 130.7

(CAr), 129.3 (CHAr), 129.2 (2 CHAr), 128.6 (CHAr), 128.5 (2 CHAr), 128.3, 124.2, 123.2, 121.1

(CHAr), 118.1, 117.7 (CAr), 117.3, 114.8, 114.5, 103.5 (CHAr), 55.6 (OCH3)

MS (EI,70 eV): m/z (%) = 367 (M+, 100), 278 (5), 205 (7), 176 (9), 92 (4), 77 (4).


3-(2-Methoxyphenyl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6c

APPENDIX

viii


IR (ATR, cm-1): 3067.7 (w), 2923.1 (w), 2843.0 (w), 1717.9 (s), 1598.9

(w), 1503.0 (m), 1465.0 (s), 1279.3 (m), 1220.4 (m), 1162.0 (m), 1108.9

(m), 1060.3 (m), 969.9 (s), 896.1 (m), 756.1 (s), 700.5 (s), 655.3 (m),

549.6 (m).

1H NMR (300 MHz, CDCl3) δ 7.98 – 7.73 (m, 1H, CHAr), 7.43 – 7.35 (m, 3H, CHAr),

7.34 – 7.21 (m, 6H, CHAr), 7.16 (dd, 3J = 7.7, 4J = 1.7 Hz, 1H, CHAr), 7.02 – 6.88 (m, 3H,

CHAr), 3.68 (s, 3H, OCH3).

13C NMR (75 MHz, CDCl3) δ 155.8 (C-OCH3), 154.0 (C=O), 151.6, 145.5, 131.3, 130.4 (CAr),

130.4 (CHAr), 129.8 (CHAr), 128.8 (2CHAr), 128.5 (CHAr ), 128.3 (2 CHAr), 128.0 (CHAr), 126.8

(CAr), 124.0, 123.1, 120.5 (CHAr), 118.4, 117.9 (CAr), 117.2, 112.0, 102.9 (CHAr), 55.8 (OCH3).

MS (EI,70 eV): m/z (%) = 367 (M+, 100), 336 (35), 261 (25), 205 (5), 176 (10), 139 (9), 77

(6).


2,3-Diphenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6d

White solid, 52% (52.6 mg). M.p.: 215–216 °C.

IR (ATR, cm-1): 3051.9 (w), 2922.3 (w), 2849.8 (w), 1714.0 (s),

1590.1 (w), 1495.0 (m), 1468.7 (m), 1390.6 (m), 1352.7 (m), 1224.1

(m), 1165.9 (m), 1110.5 (m), 1063.1 (s), 760.2 (s), 690.5 (s), 558.7

(m).

1H NMR (300 MHz, CDCl3) δ 7.92 – 7.75 (m, 1H, CHAr), 7.51 – 7.13 (m, 13H, CHAr), 6.95 (s,

1H, CHAr).

13C NMR (75 MHz, CDCl3) δ 154.1 (C=O), 151.6, 145.4, 137.5, 131.1, 130.7 (CAr), 129.3

(2CHAr), 128.7 (2 CHAr ), 128.7 (CHAr ), 128.7 (2 CHAr ), 128.5 (CHAr ), 128.5 (2 CHAr ), 128.3,

124.2, 123.12 (CHAr), 118.1, 117.7 (CAr), 117.2, 103.5 (CHAr).

MS (EI,70 eV): m/z (%) = 337 (M+, 100), 307 (5), 291 (13), 278 (5), 205 (12), 176 (10), 146

(8), 77 (11).

HRMS (+ESI, 180 eV): calcd for C23H15O2N1 ([M+H]+): 338.11773, found: 338.11756.

3-(4-Fluorophenyl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6e

APPENDIX

ix


IR (ATR, cm-1): 3412.0 (w), 3096.6 (w), 3069.1 (w), 1710.4 (w),

1609.2 (w), 1507.4 (s), 1467.2 (m), 1355.7 (m), 1220.4 (s), 1117.2

(m), 1064.2 (m), 977.5 (m), 845.3 (m), 756.7 (s), 695.1 (m), 553.3

(s).

1H NMR (300 MHz, CDCl3) δ 7.84 (dt, 3J = 7.6, 4J = 1.1 Hz, 1H, CHAr), 7.41 (dd, 3J = 4.7,

4J = 1.0 Hz, 2H, CHAr), 7.38 – 7.15 (m, 8H, CHAr), 7.13 – 7.02 (m, 2H, CHAr), 6.93 (s, 1H,

CHAr).

19F NMR (282 MHz, CDCl3) δ -112.40.

13C NMR (75 MHz, CDCl3) δ 162.4 (d, 1J = 248.7 Hz, CF), 154.2 (C=O), 151.6, 145.5, 133.5

(d, 4J = 3.3 Hz), 130.9, 130.8 (CAr), 130.4 (d, 3J = 8.8 Hz, 2 CHAr ), 129.3 (2 CHAr ), 128.7

(CHAr ), 128.6 (2 CHAr ), 128.4, 124.3, 123.2 (CHAr), 118.2, 117.6 (CAr), 117.3 (CHAr ), 115.8

(d, 2J = 23.0 Hz, 2 CHAr ), 103.6 (CHAr).

MS (EI,70 eV): m/z (%) = 355 (M+, 100), 309 (11), 224 (6), 205 (8), 176 (9), 155 (5), 95 (7).

77 (2).

2-Phenyl-3-(3-(trifluoromethyl)phenyl)chromeno[3,4-b]pyrrol-4(3H)-one 2.6f


IR (ATR, cm-1): 3059.1 (w), 2922.3 (w), 2851.1 (w), 1713.6 (s),

1612.3 (w), 1498.5 (w), 1463.6 (m), 1401.8 (w), 1330.0 (s), 1251.2

(w), 1166.3 (m), 1125.0 (s), 1064.6 (s), 987.7 (m), 818.9 (m),

765.3 (s), 698.6 (s), 654.4 (m), 550.0 (m).


7.58 – 7.45 (m, 3H, CHAr), 7.45 – 7.38 (m, 2H, CHAr)), 7.38 – 7.22 (m, 4H, CHAr), 7.22 – 7.12

(m, 2H, CHAr), 6.96 (s, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -62.73.

13C NMR (75 MHz, CDCl3) δ 154.1 (C=O), 151.6, 145.5, 137.8 (CAr), 132.1(CHAr), 131.2

(CAr), 131.2 (q, 2J = 33.1 Hz, CAr-CF3), 130.5 (CAr), 129.4 (2 CHAr ), 129.3 (CHAr ), 128.9

(CHAr), 128.7 (2 CHAr ), 128.6, 125.8 (q, 3J = 3.8 Hz), 125.4 (q, 3J = 3.6 Hz), 124.3, 123.9

(CHAr), 123.58 (q, 1J = 270.2 Hz, CF3), 118.0, 117.4 (CAr), 117.3, 104.1 (CHAr).

MS (EI,70 eV): m/z (%) = 405 (M+, 100), 384 (36), 274 (4), 205 (11), 176 (9), 145 (7), 75 (3).

HRMS (EI, 70 eV): calcd for C24H14F3O2N1 ([M]+): 405.09711, found: 405.09668.

APPENDIX

x

4-(4-Oxo-2-phenylchromeno[3,4-b]pyrrol-3(4H)-yl)benzonitrile 2.6g

Yellow solid, 40% (43.3 mg). M.p.: 233–234 °C.

IR (ATR, cm-1): 3096.1 (w), 3067,6 (w), 3046.2 (w), 2241.8 (w),

2232.5 (w), 1719.4 (m), 1704.5 (s), 1600.6 (w), 1507.9 (m),

1466.4 (m), 1399.7 (m), 1355.2 (w), 1223.5 (w), 1065.2 (m),

977.7 (m), 854.4 (m), 756.5 (s), 696.4 (m), 566.9 (m).


7.46 – 7.27 (m, 8H, CHAr), 7.16 (dd, 3J = 7.8, 4J = 1.7 Hz, 2H, CHAr), 6.97 (s, 1H, CHAr).

13C NMR (75 MHz, CDCl3) δ 154.1 (C=O), 151.6, 145.3, 141.2 (CAr), 132.6 (2 CHAr), 131.7,

130.3 (CAr), 129.7 (2 CHAr), 129.3 (2 CHAr ), 129.1 (CHAr ), 128.8 (3 CHAr ), 124.5, 123.3

(CHAr), 117.9 (CAr), 117.4 (CHAr), 117.3, 112.5 (CAr), 104.5 (CHAr). (one signal could not be

detected)

MS (EI,70 eV): m/z (%) = 362 (M+, 100), 316 (12), 277 (1), 230 (4), 203 (6), 176 (8), 152 (6),

75 (4).


3-Benzyl-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6h


IR (ATR, cm-1): 3130.8 (w), 3025.7 (w), 2962.9 (w), 2850.9 (w),

1702.9 (s), 1496.5 (m), 1427.0 (m), 1257.1 (m), 1202.5 (m), 1010.3

(m), 963.0 (m), 892.9 (m), 813.5 (m), 751.8 (s), 727.5 (s), 689.9 (s),

648.6 (m), 584.0 (m).

1H NMR (250 MHz, CDCl3) δ 7.79 (dd, 3J = 7.0, 4J = 1.0 Hz, 1H, CHAr), 7.50 – 7.35 (m, 7H,

CHAr), 7.35 – 7.15 (m, 4H, CHAr), 6.93 (dd, 3J = 7.2, 4J = 2.3 Hz, 2H, CHAr), 6.77 (s, 1H, CHAr),

5.77 (s, 2H, CH2).

13C NMR (63 MHz, CDCl3) δ 154.9 (C=O), 151.4, 145.9, 138.1, 131.2, 130.4 (CAr), 129.5 (2

CHAr), 129.1 (CHAr), 128.7 (2 CHAr), 128.5 (2 CHAr), 127.9 (CHAr), 127.3 (CHAr), 126.4

(2CHAr), 124.1, 122.9 (CHAr), 117.7 (CAr), 117.1, 103.3 (CHAr), 49.1 (CH2) (One signal could

not be detected).

MS (EI,70 eV): m/z (%) = 351 (M+, 76), 334 (4), 260 (4), 232 (7), 203 (5), 176 (6), 157 (3), 91

(100), 65 (10).


APPENDIX

xi

3-Phenethyl-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6i


IR (ATR, cm-1): 3064.6 (w), 3025.6 (w), 2924.7 (w), 2860.8 (w),

1703.1 (s), 1603.2 (w), 1504.7 (w), 1465.5 (m), 1356.5 (m), 1198.2

(m), 1110.2 (m), 1070.7 (m), 953.6 (m), 757.1 (s), 693.8 (s), 652.7

(m).


CHAr), 7.34 – 7.20 (m, 3H, CHAr), 7.21 – 7.08 (m, 3H, CHAr), 6.99 – 6.82 (m, 2H, CHAr), 6.62

(s, 1H, CHAr), 4.66 (dd, 3J = 8.2, 3J = 6.8 Hz, 2H, NCH2CH2), 3.10 – 2.96 (m, 2H, NCH2CH2).

13C NMR (63 MHz, CDCl3) δ 155.5 (C=O), 151.8, 146.2, 138.2, 131.6, 130.7 (CAr), 129.8 (2

CHAr , 129.3 (CHAr ), 129.3 (2 CHAr ), 129.0 (2 CHAr ), 128.8 (2 CHAr ), 128.3, 126.9, 124.5,

123.4 (CHAr), 118.2 (CAr), 117.5 (CHAr), 116.9 (CAr), 103.2 (CHAr), 47.9 (NCH2CH2), 38.5

(NCH2CH2).

MS (EI,70 eV): m/z (%) = 365 (M+, 41), 274 (44), 261 (100), 244 (4), 230 (16), 202 (14), 152

(3), 91 (6), 65 (3).


3-(4-Fluorobenzyl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one 2.6j


IR (ATR, cm-1): 3114.5 (w), 3054.4 (w), 2943.7 (w), 1703.7 (s),

1604.6 (w), 1506.2 (s), 1465.1 (s), 1381.6 (w), 1295.3 (m), 1208.2

(s), 1113.9 (s), 1040.5 (s), 949.6 (m), 894.5 (m), 765.2 (s), 698.2 (s),

651.5 (m), 538.4 (m).

1H NMR (300 MHz, CDCl3) δ 7.82 – 7.75 (m, 1H, CHAr), 7.49 – 7.43

(m, 3H, CHAr), 7.43 – 7.34 (m, 4H, CHAr), 7.33 – 7.27 (m, 1H, CHAr), 6.90 – 6.86 (m, 4H,

CHAr), 6.76 (s, 1H, CHAr), 5.73 (s, 2H, CH2).

19F NMR (282 MHz, CDCl3) δ -115.07.

13C NMR (63 MHz, CDCl3) δ 162.2 (d, 1J = 245.7 Hz, CF), 155.2 (C=O), 151.6, 146.0, 133.9

(d, 4J = 3.2 Hz), 131.2, 130.7 (CAr), 129.6 (2 CHAr ), 129.4 (CHAr ), 128.9 (2 CHAr ), 128.48 (d,

3J = 8.1 Hz, 2 CHAr ), 128.2, 124.3, 123.1 (CHAr), 117.8 (CAr), 117.3 (CHAr), 117.1 (CAr), 115.6

(d, 2J = 21.6 Hz, 2 CHAr ), 103.6 (CHAr), 48.5 (CH2).

MS (EI,70 eV): m/z (%) = 369 (M+, 70), 260 (4), 232 (6), 203 (4), 176 (5), 109 (100), 83 (7).

APPENDIX

xii


2-Phenyl-3-(3-(trifluoromethyl)benzyl)chromeno[3,4-b]pyrrol-4(3H)-one 2.6k


IR (ATR, cm-1): 3119.1 (w), 3067.1 (w), 2981.0 (w), 2851.0

(w), 1707.7 (s), 1504.7 (m), 1427.7 (m), 1325.6 (s), 1202.7 (m),

1118.5 (s), 1071.8 (m), 1037.2 (m), 1016.3 (m), 894.9 (m), 817.7

(m), 759.4 (s), 694.5 (s), 653.9 (s), 557.3 (m).

1H NMR (300 MHz, CDCl3) δ 7.86 – 7.70 (m, 1H, CHAr), 7.54 – 7.27 (m, 10H, CHAr), 7.17 (d,3

J = 7.8 Hz, 1H, CHAr), 7.09 (s, 1H, CHAr), 6.78 (s, 1H, CHAr), 5.81 (s, 2H, CH2).

19F NMR (282 MHz, CDCl3) δ -62.70.

13C NMR (63 MHz, CDCl3) δ 155.3 (C=O), 151.6, 146.1, 139.1, 131.0 (CAr), 130.9 (q,

2J = 32.5 Hz, C-CF3), 130.8 (CAr), 130.2 (CHAr ), 129.6 (2 CHAr ), 129.6, 129.3 (CHAr ), 129.1

(2 CHAr), 128.3 (CHAr), 124.5 (q, 3J = 8.1 Hz, CHAr), 124.4 (CHAr), 123.8 (q, 1J = 273 Hz, CF3),

123.7 (q, 3J = 7.7 Hz, CHAr), 123.2 (CHAr), 117.8 (CAr), 117.3 (CHAr), 177.1 (CAr), 103.8

(CHAr), 48.7 (CH2).

MS (EI,70 eV): m/z (%) = 419 (M+, 100), 398 (13), 274 (9), 260 (27), 232 (27), 203 (10), 176

(11), 159 (37), 109 (12), 75 (4).


3-(3,4-Dimethoxybenzyl)-2-(4-fluorophenyl)chromeno[3,4-b]pyrrol-4(3H)-one 2.6l


1H NMR (300 MHz, CDCl3) δ 7.80 – 7.73 (m, 1H, CHAr),

7.45 – 7.33 (m, 4H, CHAr), 7.33 – 7.25 (m, 1H, CHAr),

7.23 – 7.09 (m, 2H, CHAr), 6.72 (s, 1H. CHHAr), 6.67 (d,

3J = 8.3 Hz, 1H, CHAr), 6.53 (d, 4J = 2.0 Hz, 1H, CHAr), 6.43

(dd,3J = 8.2, 4J = 2.0 Hz, 1H, CHAr), 5.67 (s, 2H, CH2), 3.79 (s,

3H, OCH3), 3.72 (s, 3H, OCH3).

19F NMR (282 MHz, CDCl3) δ -111.39.

13C NMR (75 MHz, CDCl3) δ 163.3 (d, 1J = 250.0 Hz, CF), 155.2 (C=O), 151.5, 149.0, 148.5,

144.8 (CAr), 131.6 (d, 3J = 8.3 Hz, 2CHAr), 130.6 (CHAr), 130.5 (CAr), 127.5 (d, 4J = 3.5 Hz,

CAr), 124.3, 123.1, 119.2 (CHAr), 117.8 (CAr), 117.2 (CHAr), 117.1 (CAr), 116.1 (d, 2J = 21.7 Hz,

2CHAr), 111.3, 110.3, 103.6 (CHAr), 55.9, 55.9 (OCH3), 48.8 (CH2).

APPENDIX

xiii

MS (EI,70 eV): m/z (%) = 429 (M+, 18), 151 (100), 107 (7), 78 (3).


2-(4-(Tert-butyl)phenyl)-3-(4-fluorobenzyl)chromeno[3,4-b]pyrrol-4(3H)-one 2.6m


IR (ATR, cm-1): 3074.1 (w), 2961.9 (w), 2866.9 (w), 1720.6 (s),

1605.8 (m), 1508.8 (m), 1475.7 (m), 1358.2 (m), 1219.9 (m), 1156.6

(m), 1083.2 (m), 1032.4 (m), 970.7 (m), 765.3 (s), 652.1 (m), 575.9

(m), 526.5 (m).


(m, 2H, CHAr), 7.43 – 7.36 (m, 2H, CHAr), 7.36 – 7.27 (m, 3H, CHAr),

6.95 – 6.84 (m, 4H, CHAr), 6.75 (s, 1H, CHHAr), 5.73 (s, 2H, CH2), 1.37 (s, 9H, C(CH3)3).

19F NMR (282 MHz, CDCl3) δ -115.21.

13C NMR (75 MHz, CDCl3) δ 162.1 (d, 1J = 245.6 Hz, CF), 155.1 (C=O), 152.7, 151.6, 146.2,

134.1 (d, 4J = 3.2 Hz, CAr), 130.7 (CAr), 129.3 (2CHAr ), 128.4 (d, 3J = 8.1 Hz, 2CHAr ), 128.2

(CAr), 128.1 (CHAr), 125.9 (2CHAr ), 124.2, 123.1 (CHAr), 117.8 (CAr), 117.2 (CHAr), 116.9

(CAr), 115.51 (d, 2J = 21.5 Hz, 2CHAr), 103.4 (CHAr), 48.6 (CH2), 34.9 (C(CH3)3), 31.4 (3C,

C(CH3)3).

MS (EI,70 eV): m/z (%) = 425 (M+, 94), 410 (21), 301 (26), 273 (6), 109 (100), 83 (6).


2-(4-(Tert-butyl)phenyl)-3-phenethylchromeno[3,4-b]pyrrol-4(3H)-one 2.6n


IR (ATR, cm-1): 3030.4 (w), 2962.0 (w), 2921.1 (w), 2847.9 (w),

1704.6 (s), 1514.5 (w), 1490.3 (m), 1452.8 (m), 1398.2 (m),

1284.0 (m), 1070.4 (m), 1014.0 (m), 942.9 (w), 764.3 (s), 700.6

(s), 659.3 (m), 576.7 (m), 532.6 (w).


7.50 – 7.33 (m, 4H, CHAr), 7.33 – 7.11 (m, 6H, CHAr), 7.02 – 6.93 (m, 2H, CHAr), 6.62 (s, 1H,

CHHAr), 4.79 – 4.59 (m, 2H, NCH2CH2), 3.12 – 2.76 (m, 2H, NCH2CH2), 1.40 (s, 9H, C(CH3)3).

13C NMR (75 MHz, CDCl3) δ 155.2 (C=O), 152.3, 151.6, 145.9, 138.0, 130.4 (CAr), 129.3

(2CHAr), 129.0 (2CHAr), 128.5 (2CHAr), 128.3 (CAr), 127.9, 126.6 (CHAr), 125.7 (2CHAr),

APPENDIX

xiv

124.1, 123.1 (CHAr), 117.9 (CAr), 117.2 (CHAr), 116.5 (CAr), 102.7 (CHAr), 47.6 (NCH2CH2),

38.3 (NCH2CH2), 34.9 (C(CH3)3), 31.4 (3C, C(CH3)3).

MS (EI,70 eV): m/z (%) = 421 (M+, 75), 317 (77), 302 (84), 274 (100), 230 (7), 202 (8), 105

(9), 77 (9), 57 (36), 41 (10).


2-(4-methoxyphenyl)-3-phenethylchromeno[3,4-b]pyrrol-4(3H)-one 2o

Yellowish solid, 69% (81.8 mg). M.p.: 194–195 °C

1H NMR (300 MHz, CDCl3) δ 7.76 (dd, 3J = 7.7, 4J = 1.2 Hz,

1H, CHAr), 7.48 – 7.33 (m, 2H, CHAr), 7.29 (dd, 3J = 7.6,

4J = 1.7 Hz, 1H, CHAr), 7.22 – 7.10 (m, 5H, CHAr), 7.01 – 6.88

(m, 4H, CHAr), 6.57 (s, 1H, CHAr), 4.84 – 4.35 (m, 2H,

NCH2CH2), 3.88 (s, 3H, OCH3), 3.11 – 2.94 (m, 2H, NCH2CH2).

13C NMR (75 MHz, CDCl3) δ 160.2 (C-OCH3), 155.2 (C=O), 151.6, 145.8, 138.0 (CAr), 130.8

(2CHAr), 130.4 (CAr), 129.1 (2CHAr), 128.6 (2CHAr), 127.9, 126.6, 124.1 (CHAr), 123.5 (CAr),

123.1 (CHAr), 117.9 (CAr), 117.0 (CHAr), 116.4 (CAr), 114.2 (2CHAr), 102.7 (CHAr), 55.5

(OCH3), 47.56 (N CH2CH2), 38.2 (N CH2CH2).

MS (EI,70 eV): m/z (%) = 395 (M+, 57), 304 (56), 291 (100), 276 (24), 217 (12), 190 (6), 91

(6), 77 (8).


3-Phenethyl-2-propylchromeno[3,4-b]pyrrol-4(3H)-one 2.6p

Yellowish oil, 62% (61.6 mg).

IR (ATR, cm-1): 3124.1 (w), 3024.2 (w), 2959.5 (w), 2873.7 (w),

1710.7 (s), 1593.8 (w), 1491.6 (m), 1434.0 (m), 1362.3 (m),

1285.2 (m), 1208.0 (m), 1153.9 (w), 1062.2 (m), 1015.2 (m),

965.1 (m), 895.0 (m), 793.0 (m), 763.1 (s), 748.8 (s), 697.5 (s),

657.1 (m), 575.2 (m), 531.7 (m).


7.31 – 7.21 (m, 4H, CHAr), 7.15 – 7.08 (m, 2H, CHAr), 6.40 (s, 1H, CHAr), 4.67 – 4.50 (m, 2H),

3.21 – 3.03 (m, 2H), 2.38 – 2.24 (m, 2H), 1.74 – 1.55 (m, 2H, CH2), 0.96 (t, 3J = 7.3 Hz, 3H,

CH3).

APPENDIX

xv

13C NMR (63 MHz, CDCl3) δ 155.0 (C=O), 151.5, 146.3, 138.3, 130.2 (CAr), 129.2 (2CHAr),

128.7 (2CHAr), 127.7, 126.8, 124.0, 123.0 (CHAr), 118.1 (CAr), 117.2 (CHAr), 115.5 (CAr), 100.2

(CHAr), 47.1 (NCH2CH2), 38.2 (NCH2CH2), 28.3, 21.62 (CH2), 14.1 (CH3).

MS (EI,70 eV): m/z (%) = 331 (M+, 74), 240 (100), 227 (42), 212 (17), 198 (39), 181 (5), 115

(9), 91 (12), 77 (12), 65 (5).


2-Butyl-3-phenethylchromeno[3,4-b]pyrrol-4(3H)-one 2.6q


IR (ATR, cm-1): 3118.7 (w), 3025.9 (w), 2959.3 (w), 2864.4 (w),

1703.8 (s), 1612.7 (w), 1507.5 (w), 1477.5 (m), 1428.2 (m),

1358.6 (m), 1301.0 (w), 1202.2 (m), 1037.0 (m), 956.3 (w), 829.0

(m), 751.2 (s), 697.4 (m), 570.3 (m).


CHAr), 7.31 – 7.21 (m, 4H, CHAr), 7.16 – 7.07 (m, 2H, CHAr), 6.39 (s, 1H, CHAr), 4.70 – 4.49

(m, 2H, CH2), 3.10 (t, 3J = 7.3 Hz, 2H, CH2), 2.48 – 2.22 (m, 2H, CH2), 1.73 – 1.48 (m, 2H,

CH2), 1.43 – 1.25 (m, 2H, CH2), 0.93 (t, 3J = 7.3 Hz, 3H, CH3).

13C NMR (75 MHz, CDCl3) δ 154.9 (C=O), 151.4, 146.4, 138.2, 130.1 (CAr), 129.1 (2CHAr),

128.6 (2CHAr), 127.6, 126.7, 123.9, 122.9 (CHAr), 117.9 (CAr), 117.0 (CHAr), 115.3 (CAr), 100.1

(CHAr), 46.9 (NCH2CH2), 38.1 (NCH2CH2), 30.3, 25.8, 22.5 (CH2), 13.9 (CH3).

MS (EI,70 eV): m/z (%) = 345 (M+, 57), 316 (8), 254 (20), 241 (6), 212 (100), 199 (59), 167

(9), 105 (9), 91 (12), 77 (11).


2-Butyl-3-(4-fluorobenzyl)chromeno[3,4-b]pyrrol-4(3H)-one 2.6r


IR (ATR, cm-1): 3069.6 (w), 2957.3 (w), 2926.6 (w), 2855.0 (w),

1706.5 (s), 1603.4 (w), 1495.9 (m), 1432.4 (m), 1392.2 (m), 1314.5

(w), 1221.8 (m), 1159.4 (m), 1072.8 (m), 977.5 (m), 895.2 (m), 839.8

(m), 808.7 (m), 767.3 (s), 733.5 (m), 659.8 (m), 551.5 (m).


(m, 2H, CHAr), 7.32 – 7.23 (m, 1H, CHAr), 7.10 – 6.81 (m, 4H, CHAr), 6.54 (s, 1H, CHHAr), 5.73

APPENDIX

xvi

(s, 2H, CH2), 2.67 – 2.55 (m, 2H, CH2), 1.74 – 1.59 (m, 2H, CH2), 1.40 (m, 2H, CH2), 0.92 (t,

3J = 7.3 Hz, 3H, CH3).

19F NMR (282 MHz, CDCl3) δ -115.08.

13C NMR (75 MHz, CDCl3) δ 162.1 (d, 1J = 244.5 Hz, CF), 155.0 (C=O), 151.3, 146.5 (CAr),

133.3 (d, 4J = 3.3 Hz, CAr), 130.2 (CAr), 128.1 (d, 3J = 7.5 Hz, 2CHAr), 127.8 (CAr), 124.0, 122.9

(CHAr), 117.8 (CAr), 117.1, 115.9 (CHAr), 115.7 (d, 2J = 21.7 Hz, 2CHAr), 101.0 (CHAr), 47.6

(NCH2), 30.3, 26.3, 22.4 (CH2), 13.8 (CH3).

MS (EI,70 eV): m/z (%) = 349 (M+, 32), 320 (11), 307 (29), 24 (7), 224 (3), 198 (10), 109

(100), 83 (8), 63 (2).


General procedure for synthesis of Indolo[1,2-f]phenanthridines

1-Bromo-2-(phenylethynyl)benzene 3.1 (0.3 mmol), 2-bromoaniline 3.2 (0.33 mmol),

Pd(OAc)2 (0.03 mmol, 10%), XantPhos (0.03 mmol, 10%), and Cs2CO3 (0.9 mmol) were

placed in a dried pressure tube equipped with a septum. The reaction vessel was back-filled

with argon three times. Then dried and degassed DMF (4 mL) was added under argon and the

septum was replaced with a Teflon cap. The reaction mixture was allowed to stir at 120 °C for

24 h. Then the reaction mixture was cooled to room temperature and was filtered through a pad

of Celite. The filtrate was dried under reduced pressure, and the product 3.3 was obtained after

flash chromatography on a silica gel column with heptane.

Indolo[1,2-f]phenanthridine 3.3a:


IR (ATR, cm-1): 3054.8 (w), 1938.2 (w), 1594.9 (w), 1562.1 (w), 1550.6

(w), 1485 (m), 1452.2 (m), 1434.9 (s), 1355.8 (m), 1334.6 (s), 1251.6

(m), 1199.6 (m), 1107.0 (m), 1041.4 (w), 956.6 (w), 788.8 (w), 754.1

(m), 742.5 (s), 711.6 (m), 613.3 (m), 574.7 (m).


CHAr), 8.32 (dd, 3J = 8.1, 4J = 1.4 Hz, 1H, CHAr), 8.27 – 8.18 (m, 1H, CHAr), 8.18 – 8.09 (m,

1H, CHAr), 7.90 – 7.80 (m, 1H, CHAr), 7.63 – 7.52 (m, 1H, CHAr), 7.53 – 7.44 (m, 2H, CHAr),

7.44 – 7.31 (m, 3H, CHAr), 7.26 (s, 1H, CHAr).

APPENDIX

xvii

13C NMR (63 MHz, CDCl3) δ 136.3, 135.5, 134.2, 130.6 (CAr), 129.0, 128.5, 128.1 (CHAr),

127.1, 126.4 (CAr), 124.4, 124.3, 123.3, 122.7 (CHAr), 122.4 (CAr), 122.3, 122.1, 121.3, 116.6,

114.5, 96.5 (CHAr).

MS (EI,70 eV): m/z (%) = 267 (M+, 100), 239(8), 134(11), 120(4), 106(3).

HRMS (EI, 70 eV): calcd for C20H13N1 ([M]+): 267.10425, found: 267.10431.

6-Methylindolo[1,2-f]phenanthridine 3.3b:


IR (ATR, cm-1): 3120.4 (w), 3043.3 (w), 2914.1 (w), 1930.0 (w), 1593.0

(m), 1562.1 (m), 1550.6 (m), 1488.8 (m), 1446.4 (s), 1355.8 (s), 1332.6

(m), 1251.6 (m), 1195.7 (m), 1112.8 (m), 1043.4 (m), 958.5 (m), 788.8

(s), 754.1 (m), 736.7 (s), 713.6 (m), 615.2 (m), 578.6 (m).

1H NMR (300 MHz, CD2Cl2) δ 8.46 (d, 3J = 8.6 Hz, 1H, CHAr), 8.38 (d, 3J = Hz, 1H, CHAr),

8.32 – 8.24 (m, 1H, CHAr), 8.22 – 8.13 (m, 2H, CHAr), 7.88 – 7.79 (m, 1H, CHAr), 7.57 – 7.48

(m, 2H, CHAr), 7.47 – 7.42 (m, 1H, CHAr), 7.42 – 7.30 (m, 2H, CHAr), 7.29 (d, 4J = 0.7 Hz, 1H,

CHAr), 2.53 (s, 3H, CH3).

13C NMR (63 MHz, CD2Cl2) δ 135.7, 134.4, 134.4, 133.3, 130.8 (CAr), 130.3, 128.8, 128.5

(CHAr), 127.5, 126.7 (CAr), 124.9, 124.7, 123.0, 122.5 (CHAr), 122.5 (CAr), 122.2, 121.5, 116.7,

114.7, 96.4 (CHAr), 21.4 (CH3).

MS (EI,70 eV): m/z (%) = 281 (M+, 100), 252(3), 139(12).

HRMS (+ESI): calcd for C21H16N1 ([M+H]+): 282.12773, found: 282.12775.

3-Methylindolo[1,2-f]phenanthridine 3.3c:


IR (ATR, cm-1): 3114.6 (w), 3043.3 (w), 2912.1 (w), 2854.3 (w),

1907.3 (m), 1598.8 (m), 1564.1 (w), 1556.3 (w), 1494.6 (w), 1440.6

(s), 1351.9 (s), 1340.4 (m), 1253.6 (m), 1199.6 (w), 1112.8 (w),

1035.6 (m), 958.5 (m), 781.1 (m), 757.9 (s), 740.6 (s), 713.6 (s), 615.2 (m), 578.6 (m), 532.3

(s).


CHAr), 8.08 – 8.01 (m, 2H, CHAr), 7.88 – 7.80 (m, 1H, CHAr), 7.64 – 7.53 (m, 1H, CHAr),

7.44 – 7.30 (m, 4H, CHAr), 7.22 (s, 1H, CHAr), 2.53 (s, 3H, CH3).

APPENDIX

xviii

13C NMR (63 MHz, CDCl3) δ 137.8, 136.3, 135.7, 134.0, 130.7 (CAr), 129.7, 128.8 (CHAr),

127.0 (CAr), 124.3, 124.1 (CHAr), 123.9 (CAr), 123.1, 122.7 (CHAr), 122.3 (CAr), 121.9, 121.9,

121.1, 116.5, 114.3, 95.6 (CHAr), 22.0 (CH3).

MS (EI,70 eV): m/z (%) = 281 (M+, 100), 252 (3), 139 (10), 126 (4).


3,6-Dimethylindolo[1,2-f]phenanthridine 3.3d:


IR (ATR, cm-1): 3106.9 (w), 3054.8 (w), 2912.1 (w), 2850.4 (w),

2725.1 (w), 1917.0 (w), 1729.9 (w), 1598.8 (m), 1562.1 (m), 1498.5

(w), 1444.5 (s), 1350.0 (s), 1251.6 (m), 1201.5 (s), 1112.8 (m),

1033.7 (m), 960.4 (m), 867.9 (m), 823.5 (s), 784.9 (s), 756.0 (s),

736.7 (s), 713.6 (s), 655.7 (s), 613.3 (m), 574.7 (m), 538.1 (s).

1H NMR (250 MHz, CDCl3) δ 8.40 (d, 3J = 8.6 Hz, 1H, CHAr), 8.37 – 8.29 (m, 1H, CHAr), 8.07

(d, 4J = 1.2 Hz, 1H, CHAr), 8.04 – 7.95 (m, 2H, CHAr), 7.87 – 7.77 (m, 1H, CHAr), 7.42 – 7.24

(m, 4H, CHAr), 7.18 (s, 1H, CHAr), 2.51 (s, 3H, CH3), 2.50 (s, 3H, CH3).

13C NMR (63 MHz, CDCl3) δ 137.7, 135.6, 134.1, 133.8, 132.4, 130.5 (CAr), 129.5, 129.5

(CHAr), 126.9 (CAr), 124.3, 124.3 (CHAr), 123.9 (CAr), 122.6 (CHAr), 122.1 (CAr), 121.7, 121.6,

120.9, 116.3, 114.2, 95.3 (CHAr), 22.0 (CH3), 21.3 (CH3).

MS (EI,70 eV): m/z (%) = 295 (M+, 100), 278 (13), 139 (9).


6-Fluoro-3-methylindolo[1,2-f]phenanthridine 3.3e:

Yellowish solid, 55% (49.3 mg). M.p.: 165–166°C.

IR (ATR, cm -1): 3106.9 (w), 3049.1 (w), 2917.9 (w), 2856.2 (w),

2736.6 (w), 1917.0 (w), 1729.9 (w), 1606.5 (w), 1567.9 (m), 1496.6

(m), 1448.4 (m), 1429.1 (s), 1353.9 (m), 1276.7 (m), 1249.7 (m),

1203.4 (m), 1172.6 (s), 1116.6 (m), 1068.4 (m), 1041.4 (m), 960.4

(m), 948.9 (m), 867.9 (s), 823.5 (s), 788.8 (s), 754.1 (m), 734.8 (s), 713.6 (m), 655.7 (m), 611.4

(m), 572.8 (m), 536.1 (s).

1H NMR (300 MHz, CDCl3) δ 8.42 (dd, 3J = 9.2, 4J = 4.9 Hz, 1H, CHAr), 8.26 (dd, 3J = 6.5,

4J = 2.6 Hz, 1H, CHAr), 7.96 (d, 3J = 8.1 Hz, 1H, CHAr), 7.89 (dd, 3J = 10.2, 4J = 2.9 Hz, 1H,

APPENDIX

xix


(s, 3H, CH3) (signal of one H could not be detected).

19F NMR (282 MHz, CDCl3) δ -119.57.

13C NMR (75 MHz, CDCl3) δ 158.7 (d, 1J = 241.8 Hz, CF), 137.9, 135.2, 133.7 (CAr), 132.6 (d,

4J = 2.2 Hz, CAr), 130.4 (CAr), 130.3 (CHAr), 126.1 (d, 4J = 2.5 Hz, CAr), 124.3 (CHAr), 124.2

(d, 3J = 7.6 Hz, CAr), 124.1 (CAr), 122.8, 122.1, 121.9, 121.2 (CHAr), 117.7 (d, 4J = 8.2 Hz),

115.5 (d, 2J = 23.0 Hz, CHAr), 113.8 (CHAr), 110.2 (d, 2J = 23.8 Hz, CHAr), 95.7 (CHAr), 21.9

(CH3).

MS (EI,70 eV): m/z (%) = 299 (M+, 100), 270 (3), 148 (6).

HRMS (EI, 70 eV): calcd for C21H14N1F1 ([M]+): 299.11048, found: 299.11053.

3-(Tert-butyl)indolo[1,2-f]phenanthridine 3.3f:


IR (ATR, cm-1): 3122.3 (w), 3043.3 (w), 2950.7 (w), 2863.9 (w),

2742.4 (w), 2331.6 (w), 1917.0 (w), 1731.8 (w), 1606.5 (w),

1562.1 (w), 1490.8 (w), 1448.4 (s), 1440.6 (s), 1417.5 (s), 1348.1

(s), 1276.7 (m), 1259.4 (m), 1197.6 (m), 1172.6 (m), 1112.8 (m), 1072.3 (m), 1053.0 (m),

1020.2 (m), 958.5 (w), 875.6 (m), 831.2 (m), 788.8 (m), 754.1 (s), 734.8 (s), 723.2 (m), 661.5

(m), 611.4 (m), 588.2 (m), 541.9 (m).

1H NMR (300 MHz, CDCl3) δ 8.54 (d, 3J = 8.4 Hz, 1H, CHAr), 8.41 – 8.31 (m, 2H, CHAr), 8.25

(d, 4J = 1.7 Hz, 1H, CHAr), 8.06 (d, 3J = 8.4 Hz, 1H, CHAr), 7.86 – 7.76 (m, 1H, CHAr),

7.61 – 7.47 (m, 2H, CHAr), 7.41 – 7.28 (m, 3H, CHAr), 1.45 (s, 9H, C(CH3)3). (signal of one H

could not be detected).

13C NMR (63 MHz, CDCl3) δ 136.2, 135.4, 133.9, 130.6, 130.5 (CAr), 128.6 (CHAr), 126.5

(CAr), 126.2, 124.1, 123.9 (CHAr), 123.8 (CAr), 123.0 (CHAr), 122.5 (CAr), 121.8, 121.8, 120.9,

118.6, 116.5, 114.3, 95.7 (CHAr), 35.2 (C(CH3)3), 31.4 (3C, C(CH3)3).

MS (EI,70 eV): m/z (%) = 323 (M+,100), 308 (70), 293 (34), 267 (13), 140 (23).


3-(Tert-butyl)-6-methylindolo[1,2-f]phenanthridine 3.3g:

APPENDIX

xx


IR (ATR, cm-1): 3124.3 (w), 3049.1 (w), 2950.7 (w), 2863.9 (w),

2732.8 (w), 2331.6 (w), 1913.1 (w), 1731.8, 1606.5 (w), 1564.1

(m), 1488.8 (m), 1446.4 (s), 1421.4 (s), 1351.9 (s), 1280.6 (m),

1261.3 (m), 1195.7 (m), 1114.7 (m), 1066.5 (m), 1045.3 (w),

1024.1 (w), 788.8 (s), 757.9 (s), 736.7 (m), 611.4 (m), 588.2 (m), 555.4 (s).

1H NMR (300 MHz, CD2Cl2) δ 8.46 (d, 3J = 8.5 Hz, 1H, CHAr), 8.38 (d, 3J = 8.2 Hz, 1H, CHAr),

8.30 (d, 4J = 1.7 Hz, 1H, CHAr), 8.22 (s, 1H, CHAr), 8.11 (d, 3J = 8.4 Hz, 1H, CHAr), 7.83 (dd,

3J = 6.8, 4J = 1.9 Hz, 1H, CHAr), 7.61 (dd, 3J = 8.4, 4J = 1.8 Hz, 1H, CHAr), 7.49 – 7.28 (m, 3H,

CHAr), 7.24 (s, 1H, CHAr), 2.55 (s, 3H, CH3), 1.49 (s, 9H, C(CH3)3).

13C NMR (63 MHz, CD2Cl2) δ 151.6, 135.9, 134.5, 134.3, 133.2, 130.9 (CAr), 130.1 (CHAr),

127.0 (CAr), 126.7, 124.7, 124.5 (CHAr), 124.2, 122.8 (CAr), 122.2, 122.1, 121.4, 119.3, 116.8,

114.7, 95.8 (CHAr), 35.6 (C-(CH3)3), 31.7 (3C, C-(CH3)3), 21.4 (CH3).

MS (EI,70 eV): m/z (%) = 337 (M+, 100), 322 (59), 307 (32), 278 (10), 161 (5), 147 (17).


3-Fluoroindolo[1,2-f]phenanthridine 3.3h:


IR (ATR, cm-1): 3054.8 (w), 2952.6 (w), 2850.4 (w), 2734.7 (w),

2331.6 (w), 1928.6 (w), 1884.2 (w), 1731.8 (w), 1602.6 (m), 1558.3

(m), 1490.8 (m), 1440.6 (s), 1350.0 (s), 1280.6 (m), 1272.9 (m),

1195.7 (m), 1120.5 (m), 887.1 (w), 835.1 (m), 777.2 (m), 754.1 (m), 736.7 (s), 729.0 (s), 651.9

(m), 597.9 (m), 555.4 (m), 534.2 (m).

1H NMR (300 MHz, CDCl3) δ 8.42 – 8.31 (m, 1H, CHAr), 8.26 – 8.17 (m, 1H, CHAr), 8.00 (dd,

3J = 8.1, 4J = 1.3 Hz, 1H, CHAr), 7.90 (dd, 3J = 8.8, 4J = 5.7 Hz, 1H, CHAr), 7.75 – 7.62 (m, 2H,


(s, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -112.61.

13C NMR (63 MHz, CDCl3) δ 162.5 (d, 1J = 246.4 Hz, CF), 136.2, 134.6, 133.7, 130.3 (CAr),

129.4 (CHAr), 128.9 (d, 3J = 8.2 Hz, CAr), 126.2 (d, 3J = 8.7 Hz, CHAr), 124.1, 123.0 (CHAr),

122.5 (d, 4J = 2.5 Hz, CAr), 122.0, 121.89 (CHAr), 121.2 (d, 4J = 3.1 Hz, CAr), 120.9, 116.3

APPENDIX

xxi

(CHAr), 116.1 (d, 2J = 23.0 Hz, CHAr), 114.2 (CHAr), 108.4 (d, 2J = 23.2 Hz), 95.8 (d,

6J = 1.5 Hz, CHAr).

MS (EI,70 eV): m/z (%) = 285 (M+, 100), 257 (7), 143 (10).


3-Fluoro-6-methylindolo[1,2-f]phenanthridine 3.3i:


IR (ATR, cm-1): 3108.8 (w), 3051.0 (w), 2917.9 (w), 2850.4 (w),

2732.8 (w), 2325.8 (w), 1928.6 (w), 1895.8 (w), 1731.8 (w), 1614.2

(m), 1554.4 (m), 1486.9 (m), 1438.7 (m), 1350.0 (m), 1280.6 (m),

1274.8(m), 1189.9, 1120.5, 1076.1, 1041.4, 1024.1, 960.4, 900.6,

844.7(m), 784.9 (s), 736.7 (s), 653.8 (m), 632.6 (m), 615.2 (m), 607.5 (m), 574.7(m), 530.4 (m).

1H NMR (300 MHz, CDCl3) δ 8.40 – 8.21 (m, 2H, CHAr), 8.01 (dd, 3J = 8.8, 4J = 5.7 Hz, 1H,

CHAr), 7.87 (s, 1H, CHAr), 7.84 – 7.64 (m, 2H, CHAr), 7.43 – 7.28 (m, 3H, CHAr), 7.21 – 6.99

(m, 2H, CHAr), 2.46 (s, 3H, CH3).

19F NMR (282 MHz, CDCl3) δ -112.82.

13C NMR (75 MHz, CDCl3) δ 162.6 (d, 1J = 246.2 Hz, CF), 134.6, 134.2, 133.8, 132.6 (CAr),

130.4 (CHAr), 129.0 (d, 3J = 8.2 Hz, CAr), 126.3 (d, 3J = 8.7 Hz, CHAr), 124.5 (CHAr), 122.7 (d,

4J = 2.4 Hz, CAr), 122.0, 121.8 (CHAr), 121.2 (d, 4J = 3.0 Hz, CAr), 121.1, 116.3 (CHAr), 116.1

(d, 2J = 22.7 Hz, CHAr) (one signal of the doublet is overlapped with the signal at 116.3), 114.2

(CHAr), 108.5 (d, 2J = 23.3 Hz, CHAr), 95.6 (CHAr), 21.2 (CH3) (signal of one CAr could not be

detected).

MS (EI,70 eV): m/z (%) = 299 (M+, 100), 149 (8).


3-Methoxyindolo[1,2-f]phenanthridine 3.3j:


IR (ATR, cm-1): 3108.8 (w), 3043.3 (w), 2919.8 (w), 2850.4 (w),

2732.8 (w), 2323.9 (w), 2057.8 (w), 1918.9 (w), 1891.9 (w),

1731.8 (w), 1610.3 (m), 1558.3 (m), 1492.7 (s), 1427.1 (s), 1348.1

(m), 1286.4 (m), 1199.6 (m), 1120.5 (m), 1078.1 (m), 1037.6 (m), 1024.1 (m), 958.5 (m), 910.3

(m), 835.1 (m), 777.2 (m), 740.6 (s), 653.8 (m), 638.4 (m), 607.5 (m), 565.1 (m), 538.1.

APPENDIX

xxii


CHAr), 8.18 (dd, 3J = 8.1, 4J = 1.4 Hz, 1H, CHAr), 7.97 (d, 3J = 8.8 Hz, 1H, CHAr), 7.84 – 7.73

(m, 1H, CHAr), 7.60 – 7.49 (m, 2H, CHAr), 7.41 – 7.27 (m, 3H, CHAr), 7.03 (dd, 3J = 8.8,

4J = 2.5 Hz, 1H, CHAr), 3.92 (s, 3H, OCH3). (Signal of one H could not be detected).

13C NMR (63 MHz, CDCl3) δ 159.5 (C-OCH3), 136.3, 135.6, 133.8, 130.8 (CAr), 128.9 (CHAr),

128.4 (CAr), 125.8, 124.0, 122.9 (CHAr), 121.9 (CAr), 121.8, 121.6, 120.8 (CHAr), 119.8 (CAr),

116.4, 116.1, 114.2, 105.8, 94.7 (CHAr), 55.5 (OCH3).

MS (EI, 70 eV): m/z (%) = 297 (M+, 100), 282 (19), 254 (56), 226 (4), 149 (12), 126 (12).

HRMS (EI, 70 eV): calcd for C21H15N1O1 ([M]+): 297.11482, found: 297.11474.

3-Methoxy-6-methylindolo[1,2-f]phenanthridine 3.3k:


IR (ATR, cm-1): 3108.8 (w), 3045.2 (w), 2910.2 (w), 2840.8 (w),

2725.1 (w), 2325.8 (w), 2055.8 (w), 1918.9 (w), 1888.1 (w),

1731.8 (w), 1608.4 (m), 1556.3 (m), 1488.8 (m), 1431.0 (m),

1350.0 (m), 1286.4 (m), 1201.5 (m), 1130.1 (m), 1072.3 (m),

1037.6 (m), 1024.1 (m), 958.5 (m), 919.9 (m), 838.9 (m), 781.1 (s), 736.7 (s), 655.7 (m), 609.4

(m), 565.1 (m), 547.7 (s).

1H NMR (300 MHz, CDCl3) δ 8.41 – 8.21 (m, 2H), 8.06 – 7.91 (m, 2H), 7.86 – 7.72 (m, 1H),

7.57 (d, 4J = 2.3 Hz, 1H), 7.43 – 7.28 (m, 3H), 7.04 (dd, 3J = 8.8, 4J = 2.4 Hz, 2H), 3.94 (s, 3H,

OCH3), 2.47 (s, 3H, CH3).

13C NMR (63 MHz, CDCl3) δ 159.5 (C-OCH3), 135.5, 134.2, 133.7, 132.3, 130.6 (CAr), 129.8

(CHAr), 128.4 (CAr), 125.9, 124.3 (CHAr), 121.8 (CAr), 121.6, 121.4, 120.7 (CHAr), 119.9 (CAr),

116.3, 116.1, 114.2, 105.7, 94.4 (CHAr), 55.6 (OCH3), 21.2 (CH3).

MS (EI, 70 eV): m/z (%) = 311 (M+, 100), 296 (13), 268 (42), 156 (10), 133 (10).


For compounds 3.5c, 3.5d, 3.5h, 3.5i, 3.6j, 3.5g, 3.5f, 20% of PCy3·HBF4 was used instead of

XantPhos.

6-(Tert-butyl)indolo[1,2-f]phenanthridine 3.5c:

APPENDIX

xxiii


IR (ATR, cm-1): 3065.8 (w), 3043.2 (w), 2955.5 (w), 2898.7 (w), 2859.4

(w), 1953.0 (w), 1921.3 (w), 1881.4 (w), 1593.0 (m), 1552.4 (m), 1487.5

(m), 1448.4 (s), 1408.1 (w), 1357.5 (m), 1255.0 (m), 1228.8 (m), 1206.2

(m), 1120.3 (m), 1019.2 (m), 945.7 (m), 877.9 (m), 802.3 (m), 755.3 (s),

732.5 (s), 624.4 (m), 526.5 (m).

1H NMR (250 MHz, Acetone) δ 8.62 (d, 3J = 8.8 Hz, 1H, CHAr), 8.57 – 8.47 (m, 3H, CHAr),

8.33 – 8.24 (m, 1H, CHAr), 7.84 (dd, 3J = 7.1, 4J = 1.5 Hz, 1H, CHAr), 7.76 (dd, 3J = 8.8,

4J = 2.3 Hz, 1H, CHAr), 7.64 – 7.49 (m, 2H, CHAr), 7.48 – 7.25 (m, 3H, CHAr), 1.48 (s, 9H,

C(CH3)3).

13C NMR (63 MHz, Acetone) δ 147.0, 135.9, 134.8, 134.7, 131.4 (CAr), 129.3, 129.1 (CHAr),

128.1 (CAr), 127.5 (CHAr), 127.1 (CAr), 125.3, 123.8, 123.1, 122.7 (CHAr), 122.5 (CAr), 122.0,

121.8, 117.1, 115.2, 97.2 (CHAr), 35.4 (3C, C(CH3)3), 31.8 (C(CH3)3).

MS (EI, 70 eV): m/z (%) = 323 (M+, 100), 308 (90), 293 (28), 267 (16), 239 (3), 140 (22).


6-Methoxyindolo[1,2-f]phenanthridine 3.5d:


IR (ATR, cm-1): 3105.0 (w), 3043.3 (w), 2910.2 (w), 2836.9 (w), 2325.8

(w), 2053.9 (w), 1917.0 (w), 1890.0 (w), 1731.8 (w), 1620.0 (w), 1562.1

(m), 1488.8 (m), 1438.7 (m), 1357.7(m), 1288.3 (m), 1197.6 (m), 1130.1

(m), 1070.4 (m), 1041.4 (m), 1026.0 (m), 958.5 (m), 919.9 (m), 838.9

(m), 790.7 (S), 734.8 (S), 655.7 (m), 607.5 (m), 563.1(m).


8.15 (dd, 3J = 6.2, 4J = 3.1 Hz, 1H, CHAr), 8.10 – 7.93 (m, 1H, CHAr), 7.74 (d, 4J = 2.8 Hz, 1H,


(s, 3H, OCH3).

13C NMR (63 MHz, CD2Cl2) δ 156.2 (C-OCH3), 135.3, 134.1, 130.7, 130.6 (CAr), 129.0, 128.4

(CHAr), 127.2, 126.8 (CAr), 124.7 (CHAr), 123.8 (CAr), 123.3, 122.5, 121.9, 121.5, 118.0, 115.8,

114.4, 108.9, 96.3 (CHAr), 55.7 (OCH3).

MS (EI,70 eV): m/z (%) = 297 (M+, 100), 282 (25), 254 (53), 226 (5), 148 (11), 127 (14).


APPENDIX

xxiv

6-Fluoroindolo[1,2-f]phenanthridine 3.5h:


IR (ATR, cm-1): 3049.1 (w), 2140.7 (w), 1918.9 (w), 1729.9 (w), 1621.9

(w), 1567.9 (m), 1488.8 (m), 1448.4 (s), 1357.7 (m), 1276.7 (m), 1247.8

(m), 1197.6 (m), 1180.3 (s), 1139.8 (m), 1066.5 (m), 1041.4 (m), 1024.1

(m), 960.4 (m), 921.9 (m), 838.9 (m), 796.5 (s), 734.8 (s), 659.6 (m),

611.4 (m), 565.1(m).

1H NMR (300 MHz, CD2Cl2) δ 8.39 (dd, 3J = 9.2, 4J = 4.9 Hz, 1H, CHAr), 8.29 – 8.18 (m, 1H,

CHAr), 8.13 – 7.97 (m, 2H, CHAr), 7.89 (dd, 3J = 10.3, 4J = 2.9 Hz, 1H, CHAr), 7.85 – 7.75 (m,


7.19 (s, 1H, CHAr).

19F NMR (282 MHz, CD2Cl2) δ -120.10.

13C NMR (63 MHz, CD2Cl2) δ 159.2 (d, 1J = 241.2 Hz, CF), 135.3, 134.2, 132.9 (d,

4J = 2.2 Hz), 130.7 (CAr), 129.4, 128.5 (CHAr), 126.8, 126.5 (d, 4J = 2.5 Hz, CAr), 124.6 (CHAr),

124.5 (d, 3J = 7.7 Hz, CAr), 123.1, 122.8, 122.4, 121.7 (CHAr), 118.2 (d, 3J = 8.2 Hz, CHAr),

116.0 (d, 2J = 23.1 Hz, CHAr), 114.3 (CHAr), 110.6 (d, 2J = 23.9 Hz, CHAr), 96.8 (CHAr).

MS (EI, 70 eV): m/z (%) = 285 (M+, 100), 257 (8), 143 (10), 128 (4).


Indolo[1,2-f]phenanthridine-6-carbonitrile 3.5i:


IR (ATR, cm -1): 3068.3 (w), 2221.7 (m), 1593.0 (m), 1556.3 (m), 1490.8

(m), 1446.4 (s), 1409.8 (m), 1353.9 (m), 1288.3 (m), 1251.6 (m), 1207.3

(m), 1182.2 (w), 1145.6 (w), 1068.4 (w), 1045.3 (w), 1024.1 (w), 958.5

(w), 919.9 (w), 877.5 (m), 833.1 (m), 798.4 (s), 734.8 (s), 657.6 (m),

611.4 (m), 565.1 (m).


8.20 (dd, 3J = 6.4, 4J = 2.5 Hz, 1H, CHAr), 8.14 – 7.97 (m, 2H, CHAr), 7.85 – 7.77 (m, 1H,


2H, CHAr), 7.22 (s, 1H, CHAr).

APPENDIX

xxv

13C NMR (63 MHz, CD2Cl2) δ 138.9, 135.4, 134.5 (CAr), 132.3 (CHAr), 131.2 (CAr), 129.9,

128.9, 128.8 (CHAr), 126.7, 125.5 (CAr), 124.7, 123.5, 123.3 (CHAr), 123.2 (CAr), 122.9, 121.9

(CHAr), 119.4 (CN), 117.2, 114.8 (CHAr), 106.9 (CAr), 98.4 (CHAr).

MS (EI,70 eV): m/z (%) = 292 (M+, 100), 264 (10), 146 (8), 132 (9), 118 (3).


6-(Methylthio)indolo[1,2-f]phenanthridine 3.5j:


IR (ATR, cm-1): 3043.3 (w), 2917.9 (w), 1915.1 (w), 1591.1 (w), 1546.7

(m), 1490.8 (m), 1448.4 (s), 1398.2 (m), 1353.9 (m), 1288.3 (m),

1253.6(m), 1203.4 (w), 1188.0 (m), 1164.9 (m), 1114.7 (m), 1024.1 (w),

954.6 (m), 916.1 (w), 864.0 (w), 790.7 (s), 734.8 (s), 613.3 (m), 582.4

(m).



(m, 3H, CHAr), 7.33 – 7.20 (m, 2H, CHAr), 7.18 (s, 1H, CHAr), 2.51 (s, 3H, SCH3).

13C NMR (63 MHz, CD2Cl2) δ 135.3, 134.2, 134.2, 133.3, 130.8 (CAr), 129.0, 128.4, 128.3

(CHAr), 126.7, 126.7 (CAr), 124.6 (CHAr), 123.2 (CAr), 123.1, 123.0, 122.6, 122.2, 121.5, 117.4,

114.6, 96.8 (CHAr), 16.7 (SCH3).

MS (EI,70 eV): m/z (%) = 313 (M+, 100), 298 (47), 265 (12), 254 (25), 156 (9), 132 (5).

HRMS (EI, 70 eV): calcd for C21H15N1S1 ([M]+): 313.09197, found: 313.09196.

8-Fluoroindolo[1,2-f]phenanthridine 3.5g:


IR (ATR, cm-1): 3041.3 (w), 2923.7 (w), 1901.6 (w), 1604.6 (w), 1552.5

(w), 1494.6 (w), 1475.3 (m), 1442.6 (s), 1436.8 (m), 1346.1 (m), 1288.3

(m), 1251.6 (m), 1213.1 (m), 1184.1 (m), 1134.0 (m), 1074.2 (w), 1018.3

(w), 954.6 (w), 912.2 (m), 781.1 (m), 759.9 (s), 736.7 (s), 551.6 (s).


7.85 – 7.74 (m, 1H, CHAr), 7.59 – 7.41 (m, 2H, CHAr), 7.41 – 7.27 (m, 5H, CHAr).

19F NMR (282 MHz, CDCl3) δ -111.04.

APPENDIX

xxvi

13C NMR (75 MHz, CDCl3) δ 152.3 (d, 1J = 249.6 Hz, CF), 135.6 (d, 4J = 1.2 Hz), 135.5, 130.1

(CAr), 129.0, 127.9 (CHAr), 126.8, 126.5 (d, 4J = 2.7 Hz), 126.2 (d, 4J = 3.0 Hz, CAr), 124.0

(CHAr), 123.9 (d, 3J = 8.5 Hz, CHAr), 123.2 (d, 3J = 11.1 Hz, CAr), 123.0, 122.0 (CHAr), 121.7

(d, 4J = 4.1 Hz, CHAr), 120.5 (CHAr), 119.5 (d, 4J = 2.9 Hz, CHAr), 116.0 (d, 2J = 22.3 Hz,

CHAr), 115.8 (d, 2J = 26.6 Hz, CHAr), 98.0 (CHAr).

MS (EI, 70 eV): m/z (%) = 285 (M+, 100), 264 (12), 142 (9).


8-Methoxyindolo[1,2-f]phenanthridine 3.5f:


1H NMR (250 MHz, Acetone) δ 8.39 – 8.31 (m, 1H, CHAr), 8.25 (dd,

3J = 6.4, 4J = 2.6 Hz, 1H, CHAr), 8.05 (d, 3J = 7.9 Hz, 1H, CHAr),

7.80 – 7.68 (m, 2H, CHAr), 7.56 – 7.48 (m, 2H, CHAr), 7.40 (m, 2H,

CHAr), 7.35 – 7.21 (m, 3H, CHAr), 3.95 (d, 3J = 5.1 Hz, 3H).

13C NMR (63 MHz, Acetone) δ 150.7 (C-OCH3), 137.2, 136.6, 130.8 (CAr), 129.6, 128.8

(CHAr), 127.9, 127.6, 126.2 (CAr), 125.6 (CHAr), 125.0 (CAr), 124.7, 124.1, 122.0, 121.4, 120.9,

118.3, 116.9, 112.8, 98.3 (CHAr), 55.8 (OCH3).

MS (EI,70 eV): m/z (%) = 297 (M+,100), 282 (56), 252 (13), 141 (12), 126 (10), 113 (4).


1-(2-Bromophenyl)-2-(p-tolyl)-1H-indole 3.1ii


7.30 – 7.03 (m, 7H, CHAr), 6.95 (d, 3J = 8.0 Hz, 2H, CHAr),

6.90 – 6.83 (m, 1H, CHAr), 6.71 (d, 4J = 0.7 Hz, 1H, CHAr), 2.20 (s,

3H, CH3).

13C NMR (75 MHz, CDCl3) δ 141.5, 138.9, 138.4, 137.4 (CAr), 133.8, 131.5, 129.8 (CHAr),

129.7 (CAr), 129.1 (2 CHAr ), 128.5 (CAr), 128.5 (2CHAr ), 128.5 (CHAr), 124.2 (CAr), 122.3,

120.9, 120.6, 111.0, 103.1 (CHAr), 21.3 (CH3).

MS (EI, 70 eV): m/z (%) = 361 (M+,100), 281 (51), 267 (74), 190 (5), 165 (6), 133 (50).

HRMS (EI, 70 eV): calcd for C21H16N1Br1 ([M]+): 361.04606, found: 361.04591.

APPENDIX

xxvii

General procedure for synthesis of azaindolo[1,2-f]phenanthridines

3-bromo-2-(phenylethynyl)pyridine 3.6 (0.3 mmol), 2-bromoaniline 3.2 (1.1 equiv.,

0.33 mmol), Pd(PPh3)4 (10 mol%, 0.03 mmol,), XantPhos (10 mol%, 0.03 mmol), and Cs2CO3

(3 equiv., 0.9 mmol) were placed in a dried pressure tube equipped with a septum. The reaction

was back-filled with argon three times. Then dried and degassed DMF (4 mL) was added under

argon and the septum was replaced with a Teflon cap. The reaction mixture was allowed to stir

at 120 °C for 24 h. Then the reaction mixture was cooled to room temperature and was filtered

through a pad of Celite. The filtrate was dried under reduced pressure, and the product 3.7 was

obtained after flash chromatography on a silica gel column with ethyl acetate.

Pyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7a


IR (ATR, cm-1): = 3123 (w), 3099 (w), 3062 (w), 3034 (w), 1887 (w),

1598 (m), 1580 (w), 1556 (s), 1503 (w), 1488 (w), 1479 (m), 1453 (m),

1440 (s), 1414 (s), 1401 (w), 1378 (m), 1356 (m), 1325 (w), 1311 (w),

1303 (w), 1279 (m), 1236 (m), 1186 (m), 1138 (w), 1127 (w), 1110 (w), 1073 (w), 1051 (w),

1042 (w), 973 (w), 954 (w), 943 (w), 923 (w), 908 (w), 877 (w), 862 (w), 833 (w), 805 (w), 774

(w), 745 (s), 731 (w), 708 (m), 666 (w), 640 (w), 617 (m), 608 (w), 584 (w), 574 (w), 556 (w),

537 (w).

1H NMR (300 MHz, CDCl3) δ = 8.62 (dd, 3J = 4.6, 4J = 1.0 Hz, 1H, CHAr), 8.50 (d, 3J = 8.6 Hz,


7.39 – 7.09 (m, 3H, CHAr).

13C NMR (63 MHz, CDCl3) δ = 147.6 (CAr), 144.9 (CHAr), 138.3, 135.2 (CAr), 129.0, 128.9,

128.5 (CHAr), 127.0, 126.9, 125.1 (CAr), 124.9, 124.3, 123.7, 122.4 (CHAr), 121.9 (CAr), 121.3,

116.2, 116.0, 96.8 (CHAr).

MS (EI, 70 eV): m/z(%) = 268 (M+, 100), 240 (7), 214 (3), 134 (10), 120 (13), 106 (5).

HRMS (EI): Calculated for C19H12N2 (M+): 268.09950, found: 268.09952.

3-Methylpyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7d

Yellowish solid, 61% (51.6 mg). M.p.:162–164 °C.

IR(ATR, cm-1): = 3120 (w), 3093 (w), 3061 (w), 3032 (w), 2917

(w), 2851 (w), 1914 (w), 1883 (w), 1613 (w), 1598 (m), 1575 (w),

1557 (m), 1550 (w), 1493 (w), 1481 (w), 1444 (s), 1414 (s), 1375

APPENDIX

xxviii

(m), 1349 (m), 1306 (m), 1283 (m), 1238 (m), 1208 (w), 1189 (m), 1164 (w), 1149 (w), 1127

(w), 1115 (w), 1079 (m), 1039 (m), 956 (m), 943 (w), 923 (m), 913 (w), 903 (w), 873 (m), 834

(w), 810 (s), 772 (m), 755 (s), 734 (s), 714 (w), 660 (w), 651 (w), 623 (m), 610 (m), 578 (s),

545 (w), 532 (s).

1H NMR (300 MHz, CDCl3) δ = 8.72 – 8.54 (m, 1H, CHAr), 8.50 – 8.36 (m, 1H, CHAr), 8.19

(dd, 3J = 10.5, 3J = 5.7 Hz, 2H, CHAr), 7.95 – 7.78 (m, 2H, CHAr), 7.54 – 7.36 (m, 1H, CHAr),

7.34 – 7.09 (m, 4H, CHAr), 2.45 (s, 3H, CH3).

13C NMR (75 MHz, CDCl3) δ = 147.9 (CAr), 144.8 (CHAr), 138.8, 138.5, 135.3 (CAr), 129.7,

128.8 (CHAr), 126.8 (CAr), 124.8, 124.1, 123.5 (CHAr), 122.6 (CAr), 122.5 (CHAr), 121.9 (CAr),

121.0, 115.9, 115.8, 96.1 (CHAr), 22.0 (CH3). (one signal of C tertiary could not be detected).

MS (EI, 70 eV): m/z(%) = 282 (M+, 100), 266 (4), 140 (10), 128 (2), 126 (5).

HR-MS (EI): calculated for C20H14N2 (M+): 282.11515, found: 282.11477.

3-(Tert-butyl)pyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 8f


IR (ATR, cm-1): = 3060 (w), 3025 (w), 2947 (m), 2902 (w), 2860

(w), 1931 (w), 1884 (w), 1732 (w), 1615 (w), 1598 (m), 1578 (w),

1557 (m), 1504 (w), 1494 (m), 1479 (w), 1463 (w), 1443 (s), 1413

(s), 1392 (w), 1357 (w), 1348 (m), 1303 (w), 1275 (m), 1265 (m), 1242 (w), 1205 (w), 1187

(m), 1162 (w), 28 1151 (w), 1127 (w), 1115 (w), 1097 (w), 1070 (w), 1053 (w), 1039 (w), 1021

(w), 970 (w), 956 (m), 925 (w), 913 (w), 875 (m), 832 (w), 813 (m), 788 (s), 769 (m), 756 (s),

738 (s), 710 (w), 657 (w), 648 (w), 623 (s), 608 (w), 584 (m), 542 (s).

1H NMR (300 MHz, CDCl3) δ = 8.63 (d, 4J = 4.1 Hz, 1H, CHAr), 8.53 (d, 3J = 8.6 Hz, 1H,

CHAr), 8.41 – 8.29 (m, 2H, CHAr), 8.24 (d, 4J = 1.7 Hz, 1H, CHAr), 8.10 (d, 3J = 8.4 Hz, 1H,

CHAr), 7.64 – 7.48 (m, 2H, CHAr), 7.42 – 7.32 (m, 2H, CHAr), 7.22 (dd, 3J = 8.5, 4J = 4.6 Hz,

1H, CHAr), 1.47 (s, 9H, C(CH3)3).

13C NMR (75 MHz, CDCl3) δ = 152.1, 148.0 (CAr), 144.9 (CHAr), 138.5, 135.5 (CAr), 128.9

(CHAr), 127.0, 126.6 (CAr), 126.5, 124.9, 124.2, 123.6 (CHAr), 122.8, 122.4 (CAr), 121.1, 118.7,

116.1, 116.0, 96.3 (CHAr), 35.4 (C(CH3)3), 31.4 (3C, C(CH3)3).

MS (EI, 70 eV): m/z(%) = 324 (M+, 100), 309 (98), 294 (28), 290 (4), 281 (12), 268 (15), 240

(4), 154 (4), 146 (4), 140 (24), 132 (6), 126 (4), 41 (3), 39 (3).

HR-MS (EI): calculated for C23H20N2 (M+): 324.16210, found: 324.16196.

APPENDIX

xxix

3-Fluoropyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7h


IR (ATR, cm-1): = 3059 (w), 3035 (w), 1616 (m), 1603 (m), 1580

(w), 1558 (m), 1551 (m), 1489 (m), 1443 (s), 1416 (s), 1379 (w),

1349 (m), 1331 (w), 1304 (w), 1272 (m), 1245 (w), 1236 (w), 1180

(s), 1135 (w), 1128 (w), 1106 (w), 1072 (w), 1054 (w), 1032 (w), 957 (m), 933 (w), 915 (w),

892 (m), 854 (w), 819 (w), 810 (m), 784 (w), 763 (s), 755 (m), 733 (s), 706 (w), 652 (m), 631

(m), 621 (m), 606 (w), 599 (m), 583 (w), 545 (w), 533 (m).


CHAr), 8.23 – 8.11 (m, 1H, CHAr), 8.02 (dd, 3J = 8.1, 4J = 1.3 Hz, 1H, CHAr), 7.95 (dd, 3J = 8.8,

3J = 5.7 Hz, 1H, CHAr), 7.66 (dd, 3J = 10.6, 4J = 2.5 Hz, 1H, CHAr), 7.55 – 7.45 (m, 1H, CHAr),

7.32 – 7.23 (m, 2H, CHAr), 7.23 – 7.08 (m, 3H, CHAr).

19F NMR (63 MHz, CDCl3) δ = 110.77 Hz.

13C NMR (63 MHz, CDCl3) δ = 163.1 (d, 1J = 248.2 Hz, CF), 147.7 (CAr), 145.1 (CHAr), 137.5,

135.5 (CAr), 129.7 (CHAr), 129.1 (d, 3J = 8.4 Hz, CAr), 127.2 (d, 3J = 8.9 Hz, CHAr), 126.8 (CAr),

124.4, 123.7 (CHAr), 121.5 (d, 4J = 2.5 Hz, CAr), 121.1 (CHAr), 121.1 (CAr), 116.5 (d,

2J = 23.2 Hz, CHAr), 116.2, 116.0 (CHAr), 108.5 (d, 2J = 23.4 Hz, CHAr), 96.5 (d, 6J = 1.3 Hz,

CHAr).

MS (EI, 70 eV): m/z(%) = 286 (M+, 100), 258 (7), 232 (3), 195 (2), 143 (10), 129 (11), 115 (3).

HR-MS (EI): calculated for C19H11N2F1 (M+): 286.09008, found: 286.08980.

3-Methoxypyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7j


IR (ATR, cm-1): = 3089 (w), 3032 (w), 2999 (w), 2958 (w), 2930

(w), 2908 (w), 2831 (w), 1609 (s), 1601 (s), 1550 (s), 1493 (s),

1450 (s), 1438 (w), 1428 (w), 1414 (s), 1379 (w), 1347 (m), 1334

(w), 1303 (w), 1278 (s), 1244 (w), 1219 (s), 1190 (m), 1181 (w), 1141 (w), 1130 (w), 1111 (w),

1079 (w), 1073 (w), 1056 (w), 1041 (w), 1033 (w), 1021 (m), 980 (w), 971 (w), 956 (m), 912

(w), 905 (w), 883 (w), 872 (w), 865 (w), 830 (m), 823 (w), 813 (s), 785 (w), 766 (s), 753 (s),

736 (s), 705 (w), 656 (m), 634 (m), 623 (m), 607 (s), 584 (m), 555 (m), 539 (m).


CHAr), 8.08 (d, 3J = 8.1 Hz, 1H, CHAr), 7.98 (dd, 3J = 8.1, 4J = 1.0 Hz, 1H, CHAr), 7.79 (d,

APPENDIX

xxx

3J = 8.8 Hz, 1H, CHAr), 7.44 – 7.29 (m, 2H, CHAr), 7.22 – 7.12 (m, 1H, CHAr), 7.07 (dd,

3J = 8.5, 4J = 4.6 Hz, 1H, CHAr), 7.02 (s, 1H, CHAr), 6.90 (dd, 3J = 8.8, 4J = 2.4 Hz, 1H, CHAr),

3.79 (s, 3H, OCH3).

13C NMR (75 MHz, CDCl3) δ = 160.2 (CAr-OCH3), 148.0 (CAr), 144.7 (CHAr), 138.6, 135.5

(CAr), 129.1 (CHAr), 128.5, 126.8 (CAr), 126.6, 124.2, 123.5 (CHAr), 121.7 (CAr), 120.9 (CHAr),

118.6 (CAr), 116.3, 116.0, 115.6, 105.6, 95.2 (CHAr), 55.5 (OCH3).

MS (EI, 70 eV): m/z(%) = 298 (M+, 100), 283 (20), 255 (63), 227 (7), 149 (9), 127 (4), 113 (5),

99 (3). HR-MS (EI): calculated for C20H14N2O1 (M+): 298.11006, found: 298.10998.

6-Methylpyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7b


IR (ATR, cm-1): = 3124 (w), 3069 (w), 3036 (w), 2954 (w), 2916 (m),

2850 (m), 2746 (w), 1942 (w), 1900 (w), 1877 (w), 1860 (w), 1823 (w),

1795 (w), 1600 (m), 1577 (w), 1569 (m), 1553 (s), 1524 (w), 1496 (m),

1450 (s), 1416 (s), 1387 (w), 1372 (w), 1354 (m), 1324 (w), 1310 (w),

1300 (w), 1279 (m), 1236 (w), 1193 (w), 1182 (m), 1165 (w), 1145 (w), 1124 (m), 1116 (m),

1066 (w), 1042 (w), 999 (w), 972 (w), 955 (m), 937 (w), 910 (m), 883 (w), 866 (m), 853 (m),

828 (w), 801 (m), 790 (s), 772 (m), 748 (s), 730 (w), 720 (w), 710 (w), 694 (w), 660 (w), 643

(m), 620 (w), 576 (s), 540 (m).

1H NMR (300 MHz, CDCl3) δ = 8.60 (s, 1H, CHAr), 8.39 (d, 3J = 8.5 Hz, 1H, CHAr),

8.13 – 7.95 (m, 3H, CHAr), 7.91 (s, 1H, CHAr), 7.54 – 7.35 (m, 2H, CHAr), 7.30 (s, 1H, CHAr),

7.19 (d, 3J = 7.0 Hz, 2H, CHAr), 2.39 (s, 3H, CH3).

13C NMR (75 MHz, CDCl3) δ = 147.2 (CAr), 144.4 (CHAr), 139.9, 138.3, 133.1, 133.0 (CAr),

129.8, 128.8, 128.3 (CHAr), 127.0, 125.0 (CAr), 125.0, 124.4, 122.4 (CHAr), 121.7 (CAr), 121.3,

116.0, 115.7, 96.2 (CHAr), 21.2 (CH3).

MS (EI, 70 eV): m/z(%) = 282 (M+, 100), 266 (4), 252 (3), 140 (16), 126 (5), 113 (2), 100 (2).

HRMS (EI): calculated for C20H14N2 (M+): 282.11515, found: 282.11484.

3,6-Dimethylpyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7e

APPENDIX

xxxi


IR (ATR, cm-1): = 3154 (w), 3115 (w), 3097 (w), 3056 (w), 3025

(w), 3004 (w), 2952 (w), 2917 (m), 2851 (w), 1920 (w), 1898 (w),

1854 (w), 1613 (w), 1601 (m), 1569 (w), 1549 (s), 1491 (m), 1481

(w), 1434 (w), 1416 (s), 1373 (w), 1352 (w), 1300 (w), 1281 (m),

1262 (w), 1237 (m), 1205 (w), 1192 (m), 1152 (w), 1121 (w), 1099 (w), 1069 (w), 1041 (m),

957 (m), 929 (w), 906 (w), 877 (m), 867 (w), 817 (w), 806 (s), 784 (s), 754 (s), 741 (w), 716

(w), 694 (w), 660 (m), 629 (w), 622 (w), 590 (m), 578 (m), 560 (w), 533 (s).

1H NMR (300 MHz, CDCl3) δ = 8.59 (s, 1H, CHAr), 8.36 (d, 3J = 8.5 Hz, 1H, CHAr), 7.98 (d,

3J = 8.5 Hz, 1H, CHAr), 7.88 (d, 3J = 8.3 Hz, 2H, CHAr), 7.79 (s, 1H, CHAr), 7.35 – 6.87 (m, 4H,

CHAr), 2.45 (s, 3H, CH3), 2.38 (s, 3H, CH3).


129.6, 129.5 (CHAr), 126.8, 126.7 (CAr), 124.8, 124.2 (CHAr), 122.6 (CAr), 122.4 (CHAr), 121.7

(CAr), 120.9 (CHAr), 115.6 (2 CHAr ), 95.6 (CHAr), 22.0 (CH3), 21.2 (CH3).

MS (EI, 70 eV): m/z(%) = 296 (M+, 100), 279 (11), 266 (2), 148 (6), 147 (3), 146 (3), 140 (7),

126 (2). HR-MS (EI): calculated for C21H16N2 ([M+1]+1): 297.13862, found: 297.13882.

3-(Tert-butyl)-6-methylpyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7g

Yellow solid, 32% (32.4 mg). M.p. 197–199 °C.

IR (ATR, cm-1): = 3033 (w), 2956 (m), 2914 (w), 2864 (w), 1615

(w), 1600 (w), 1569 (w), 1556 (m), 1548 (m), 1489 (w), 1482 (w),

1460 (w), 1444 (w), 1427 (w), 1414 (s), 1391 (w), 1379 (w), 1357

(m), 1353 (m), 1301 (w), 1280 (m), 1263 (m), 1240 (w), 1202 (w),

1187 (w), 1159 (w), 1131 (w), 1121 (w), 1067 (w), 1045 (w), 958 (m), 941 (w), 925 (w), 904

(w), 880 (m), 865 (w), 830 (m), 811 (w), 786 (s), 774 (s), 757 (s), 736 (w), 722 (m), 666 (w),

656 (w), 634 (w), 620 (w), 611 (w), 578 (m), 552 (s), 533 (w).

1H NMR (300 MHz, CDCl3): δ = 8.67 – 8.56 (m, 1H, CHAr), 8.49 (d, 3J = 8.5 Hz, 1H, CHAr),

8.23 – 8.07 (m, 4H, CHAr), 7.63 – 7.57 (m, 1H, CHAr), 7.36 – 7.29 (m, 2H, CHAr), 7.20 (dd,

3J = 8.5 Hz, 4J = 4.5 Hz, 1H, CHAr), 2.51 (s, 3H, CH3), 1.48 (s, 9H, C(CH3)3).

13C NMR (75 MHz, CDCl3): δ = 152.0, 147.9 (CAr), 144.8 (CHAr), 138.4, 133.4, 133.1 (CAr),

129.8 (CHAr), 126.7 (CAr), 126.3, 125.0, 124.3 (CHAr), 122.9, 122.3 (CAr), 121.0, 118.6, 116.0,

115.8, 96.0 (CHAr), 35.4 (C(CH3)3), 31.5 (CH3), 21.3 (3C, C(CH3)3) (one signal of CAr could

not be detected).

APPENDIX

xxxii

MS (EI, 70 eV): m/z(%) = 338 (M+, 100), 323 (85), 308 (29), 295 (9), 282 (11) , 266 (3), 161

(7), 153 (4), 152 (3), 147 (23), 140 (8), 139 (5), 133 (4), 41 (5), 39 (4). HR-MS (EI): calculated

for C24H22N2 (M+): 338.17775, found: 338.17773.

3-Fluoro-6-methylpyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7i


IR (ATR, cm-1): = 3033 (w), 2956 (m), 2914 (w), 2864 (w), 1615

(w), 1600 (w), 1569 (w), 1556 (m), 1548 (m), 1489 (w), 1482 (w),

1460 (w), 1444 (w), 1427 (w), 1414 (s), 1391 (w), 1379 (w), 1357

(m), 1353 (m), 1301 (w), 1280 (m), 1263 (m), 1240 (w), 1202 (w),

1187 (w), 1159 (w), 1131 (w), 1121 (w), 1067 (w), 1045 (w), 958 (m), 941 (w), 925 (w), 904

(w), 880 (m), 865 (w), 830 (m), 811 (w), 786 (s), 774 (s), 757 (s), 736 (w), 722 (m), 666 (w),

656 (w), 634 (w), 620 (w), 611 (w), 578 (m), 552 (s), 533 (w).


8.11 – 8.01 (m, 2H, CHAr), 7.84 (s, 1H, CHAr), 7.76 – 7.69 (m, 1H, CHAr), 7.35 – 7.22 (m, 3H,

CHAr), 7.19 (dd, 3J = 8.4 Hz, 4J = 2.3 Hz, 1H, CHAr), 2.48 (s, 3H, CH3).

19F NMR (63 MHz, CDCl3) δ = 110.92.


133.3, 133.3 (CAr), 130.5 (CHAr), 129.1 (d, 3J = 8.4 Hz, CAr), 127.2 (d, 3J = 8.9 Hz, CHAr), 124.6

(CHAr), 121.6 (d, 4J = 2.4 Hz, CAr), 121.0 (CHAr), 120.9 (d, 4J = 3.0 Hz, CAr), 116.4 (d,

2J = 23.2 Hz, CHAr), 116.0, 115.8 (CHAr), 108.5 (d, 2J = 23.4 Hz, CHAr), 96.1 (CHAr), 21.2

(CH3). (Signal of one CAr could not be detected).

MS (EI, 70 eV): m/z(%) = 338 (M+, 100), 323 (85), 308 (29), 295 (9), 282 (11), 266 (3), 161

(7), 153 (4), 147 (23), 140 (8), 139 (5), 133 (4), 41 (5), 39 (4). HR-MS (EI): calculated for

C20H13F1N2 (M+): 338.17775, found: 338.17773.

3-Methoxy-6-methylpyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7k


IR (ATR, cm-1): = 3094 (w), 3029 (w), 3005 (w), 2916 (w), 2839

(w), 2054 (m), 1722 (w), 1610 (s), 1572 (w), 1546 (s), 1493 (s),

1467 (w), 1452 (w), 1432 (w), 1418 (s), 1378 (w), 1353 (w), 1333

(w), 1300 (w), 1282 (s), 1243 (w), 1223 (s), 1194 (m), 1188 (m),

1152 (w), 1125 (w), 1074 (w), 1028 (s), 959 (m), 936 (w), 906 (w), 860 (w), 833 (m), 819 (m),

APPENDIX

xxxiii

803 (w), 782 (s), 773 (m), 751 (s), 710 (w), 682 (w), 668 (w), 633 (m), 621 (w), 587 (w), 579

(w), 545 (s).

1H NMR (300 MHz, CDCl3) δ = 8.57 (s, 1H, CHAr), 8.47 (d, 3J = 8.5 Hz, 1H, CHAr), 8.12 (d,

3J = 8.5 Hz, 1H, CHAr), 7.99 (d, 3J = 8.8 Hz, 1H, CHAr), 7.93 (s, 1H, CHAr), 7.53 (d, 4J = 2.4 Hz,

1H, CHAr), 7.31 (dd, 3J = 8.5, 4J = 1.1 Hz, 1H, CHAr), 7.24 – 7.13 (m, 2H, CHAr), 7.07 (dd,

3J = 8.8, 4J = 2.4 Hz, 1H, CHAr), 3.95 (s, 3H, OCH3), 2.46 (s, 3H, CH3).

13C NMR (63 MHz, CDCl3) δ = 160.5 (C-OCH3), 147.2 (CAr), 143.7 (CHAr), 139.1, 133.3 (CAr),

130.2 (CHAr), 128.8, 127.0 (CAr), 126.9, 124.5 (CHAr), 121.7 (CAr), 121.4 (CHAr), 118.6 (CAr),

116.4, 115.9, 115.4, 105.8, 94.5 (CHAr), 55.7 (OCH3), 21.3 (CH3). (one signal of CAr could not

be detected).

MS (EI, 70 eV): m/z(%) = 312 (M+, 100), 297 (16), 269 (53), 253 (4), 239 (2), 156 (10), 134

(7), 121 (3), 120 (3), 107 (2). HR-MS (EI): calculated for C21H16N2O1 (M+): 312.12571, found:

312.12596.

6-Fluoropyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.7c (3.8e)


IR (ATR, cm-1): = 3131.1 (w), 3056.8 (w), 3031.7 (w), 2920.8 (w),

2850.5 (w), 1942.2 (w), 1889.7 (w), 1573.4 (m), 1557.6 (s), 1496.3 (m),

1452.2 (m), 1420.5 (s), 1280.2 (m), 1243.7 (m), 1201.1 (m), 1174.1 (m),

1137.7 (m), 1108.0 (w), 1168.8 (m), 957.1 (m), 909.6 (m), 856.1 (m),

806.8 (m), 782.8 (m), 746.5 (s), 577.9 (m).



1H, CHAr), 7.90 (dd, 3J = 10.0, 4J = 2.8 Hz, 1H, CHAr), 7.60 – 7.47 (m, 2H, CHAr), 7.36 (s, 1H,

CHAr), 7.28 – 7.16 (m, 2H, CHAr).

19F NMR (282 MHz, CDCl3) δ -118.20.


131.8 (d, 4J = 2.1 Hz, CAr), 129.3, 129.0 (CHAr), 126.8 (CAr), 126.2 (d, 4J = 2.5 Hz, CAr), 125.6

(CAr), 125.1 (CHAr), 124.0 (d, 3J = 7.7 Hz, CAr), 122.7, 120.7 (CHAr), 117.5 (d, 3J = 8.1 Hz,

CHAr), 116.5 (CHAr), 116.1 (d, 2J = 23.2 Hz, CHAr), 110.6 (d, 2J = 23.9 Hz, CHAr), 97.1 (CHAr).

MS (EI, 70 eV): m/z(%) = 286 (M+, 100), 258 (7), 232 (5), 208 (2), 195 (3), 168 (3), 143 (6),

128 (3), 99 (2), 87 (2), 75 (2), 62 (5), 51 (3), 39 (3).

APPENDIX

xxxiv

HR-MS (EI): calculated for C19H11N2F1 (M+): 286.09008, found: 286.09014

6-Methoxypyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.8b


IR (ATR, cm-1): = 3133.5 (w), 3055.6 (w), 2919.6 (w), 2849.1 (w),

1957.7 (w), 1925.7 (w), 1900.2 (w), 1726.6 (w), 1616.8 (m), 1606.1 (m),

1569.7 (m), 1552.5 (s), 1500.3 (m), 1453.4 (m), 1419.4 (s), 1350.4 (m),

1218.9 (m), 1185.5 (m), 1138.4 (m), 1018.3 (m), 956.6 (m), 850.5 (m),

789.6 (m), 755.3 (s), 694.9 (m), 583.2 (m).


CHAr), 8.13 (d, 3J = 9.2 Hz, 1H, CHAr), 8.10 – 8.00 (m, 2H, CHAr), 7.64 (d, 4J = 2.8 Hz, 1H,

CHAr), 7.53 – 7.39 (m, 2H, CHAr), 7.32 (s, 1H, CHAr), 7.19 (dd, 3J = 8.6, 4J = 4.6 Hz, 1H, CHAr),

7.03 (dd, 3J = 9.1, 4J = 2.9 Hz, 1H, CHAr), 3.89 (s, 3H, OCH3).

13C NMR (63 MHz, CDCl3) δ = 155.7, 147.4 (CAr), 144.7 (CHAr), 137.9, 129.7 (CAr), 128.8,

128.6 (CHAr), 126.8, 126.7, 125.4 (CAr), 125.1 (CHAr), 123.3(CAr), 122.5, 120.8, 117.1, 116.0,

115.3, 108.4, 96.3 (CHAr), 55.7 (OCH3).

MS (EI, 70 eV): m/z(%) = 298 (M+, 100), 283 (37), 255 (70), 227 (11). 200 (5), 174 (4), 149

(8), 127 (7), 114 (11), 100 (5), 87 (7), 75 (4), 63 (4), 51 (4), 39 (6).

HR-MS (EI): calculated for C20H14N2O1 (M+): 298.11006, found: 298.10977.

8-Methoxypyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.8c

Yellow oil, 60% (53.6 mg).

1H NMR (300 MHz, CDCl3) δ = 8.59 (dd, 3J = 4.5, 4J = 0.9 Hz, 1H,

CHAr), 8.25 – 8.12 (m, 2H, CHAr), 8.10 – 8.03 (m, 1H, CHAr), 7.94 (dd,

3J = 8.1, 5J = 0.9 Hz, 1H, CHAr), 7.65 – 7.45 (m, 3H, CHAr), 7.39 (t,

3J = 8.1 Hz, 1H, CHAr), 7.22 – 7.07 (m, 2H, CHAr), 3.90 (s, 3H, OMe).

13C NMR (63 MHz, CDCl3) δ = 149.5, 146.9 (CAr), 144.4 (CHAr), 139.1, 129.9 (CAr), 128.9,

128.8 (CHAr), 127.3, 125.9, 125.4 (CAr), 124.9 (2CHAr), 124.7 (CHAr), 124.1 (CAr), 123.1, 116.4,

115.0, 112.1, 97.6 (CHAr), 55.9 (OCH3).

MS (EI, 70 eV): m/z(%) = 298 (M+, 100), 283 (83), 253 (13), 227 (7), 201 (4), 175 (2), 142

(10), 127 (6), 114 (7), 100 (7).

HRMS (EI): calculated for C20H14N2O1 (M+): 298.11006, found: 298.11014.

APPENDIX

xxxv

6-(Methylthio)pyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.8g


IR (ATR, cm-1): = 3031.8 (w), 3001.0 (w), 2958.0 (w), 2917.4 (w),

2849.2 (w), 1597.0 (w), 1646.3 (m), 1488.3 (w), 1449.2 (m), 1413.4 (s),

1354.0 (m), 1278.7 (m), 1189.0 (m), 1115.3 (w), 955.0 (m), 855.7 (w),

789.8 (s), 750.4 (s), 580.6 (m).


8.17 – 7.97 (m, 4H, CHAr), 7.57 – 7.42 (m, 2H, CHAr), 7.35 (dd, 3J = 8.8, 4J = 2.1 Hz, 1H,

CHAr), 7.31 (s, 1H, CHAr), 7.22 (dd, 3J = 8.5, 4J = 4.6 Hz, 1H, CHAr), 2.57 (s, 3H, SCH3).

13C NMR (75 MHz, CDCl3) δ = 147.2 (CAr), 144.6 (CHAr), 138.2, 133.5, 133.0 (CAr), 129.0,

128.8, 127.9 (CHAr), 126.4, 125.2 (CAr), 125.1, 122.8 (CHAr), 122.6 (CAr), 122.4, 121.3, 116.5,

116.2, 96.7 (CHAr), 16.8 (SCH3). (one signal of CAr could not be detected).

MS (EI, 70 eV): m/z(%) = 314 (M+, 100), 299 (52), 266 (9), 255 (28), 227 (4), 157 (13), 127

(6), 113 (3), 100 (2).

HRMS (EI): calculated for C20H14N2S1 (M+): 314.08722, found: 314.08694.

Benzo[c]pyrido[2',3':4,5]pyrrolo[1,2-f]phenanthridine 3.8h


IR (ATR, cm-1): = 3096.6 (w), 2958.7 (w), 2850.5 (w), 1954.5 (w),

1915.3 (w), 1808.3, 1713.7 (w), 1621.8 (w), 1576.9 (m), 1543.0 (m),

1416.8 (s), 1389.4 (m), 1274.8 (m), 1029.8 (m), 807 (m), 752.5 (s), 611.2

(m), 566.6 (m).

1H NMR (300 MHz, CDCl3) δ = 8.64 (d, 4J = 4.0 Hz, 1H, CHAr), 8.34 – 8.11 (m, 4H, CHAr),

7.96 – 7.84 (m, 2H, CHAr), 7.79 (d, 3J = 8.7 Hz, 1H, CHAr), 7.60 – 7.47 (m, 3H, CHAr), 7.45 (d,

5J = 0.6 Hz, 1H, CHAr), 7.43 – 7.34 (m, 1H, CHAr), 7.03 (dd, 3J = 8.5, 4J = 4.5 Hz, 1H, CHAr).


129.0, 128.7, 128.3 (CHAr), 127.6 (CAr), 127.2 (CHAr), 125.9 (CAr), 125.2, 124.7, 124.6, 124.3

(CHAr), 123.7 (CAr), 123.0, 122.1 (CHAr), 121.0 (CAr), 120.5, 114.0, 97.7 (CHAr).

MS (EI, 70 eV): m/z(%) = 318 (M+, 100), 291 (12), 237 (2), 159 (41), 144 (23), 131 (9), 105

(2), 87 (1).

HRMS (EI): calculated for C23H14N2 (M+): 318.11515, found: 318.11507.

APPENDIX

xxxvi

6-Methoxypyrido[3',2':4,5]pyrrolo[1,2-f]phenanthridine 3.9a


IR (ATR, cm-1): = 3104.4 (w), 2997.7 (w), 2930.7 (w), 2830.5 (w),

2089.0 (w), 1892.9 (w), 1713.5 (w), 1620.3 (w), 1563.3 (m), 1543.8 (s),

1499.5 (m), 1453.9 (m), 1407.9 (m), 1327 (m), 1293.2 (m), 1215.2 (m),

1075.3 (m), 1042.8 (m), 1016.0 (m), 945.9 (w), 855.2 (m), 792.4 (m),

758.9 (m), 729.0 (m), 607.9 (m), 566.3 (m).

1H NMR (300 MHz, CDCl3) δ = 10.15 (d, 3J = 9.3 Hz, 1H, CHAr), 8.50 (dd, 4J = 4.6,

4J = 1.6 Hz, 1H, CHAr), 8.24 – 7.97 (m, 3H, CHAr), 7.72 (d, 4J = 2.8 Hz, 1H, CHAr), 7.57 – 7.39

(m, 2H, CHAr), 7.34 – 7.16 (m, 2H, CHAr), 7.08 (s, 1H, CHAr), 3.95 (s, 3H, OCH3).

13C NMR (63 MHz, CDCl3) δ = 155.8 (C-OCH3), 146.9 (CAr), 141.8 (CHAr), 134.6, 129.9 (CAr),

128.4, 128.3, 128.2 (CHAr), 127.4, 125.8 (CAr), 124.3, 122.8 (CHAr), 122.7, 122.1 (CAr), 120.4,

117.5, 115.5, 107.5, 92.4 (CHAr), 55.7 (OCH3).

MS (EI, 70 eV): m/z(%) = 298 (M+, 100), 283 (34), 255 (61), 227 (7), 201 (3), 175 (2), 149

(15), 127 (16), 113 (4), 100 (5).

HRMS (EI): calculated for C20H14N2O1 (M+): 298.11066, found: 298.11047

6-Fluoropyrido[3',2':4,5]pyrrolo[1,2-f]phenanthridine 3.9b


IR (ATR, cm-1): = 3122.0 (w), 3054.0 (w), 1920.0 (w), 1884.2 (w),

1798.7 (w), 1661.0 (w), 1620.4 (w), 1567.0 (m), 1497.6 (m), 1454.6 (m),

1409.4 (m), 1329.7 (m), 1267.7 (m), 1174.5 (m), 1141.0 (m), 892.5 (m),

824.2 (m), 752.8 (m), 724.4 (m), 662.7 (w), 593.9 (m), 566.3 (m).

1H NMR (300 MHz, CDCl3) δ = 10.26 (dd, 3J = 9.3, 3J = 5.5 Hz, 1H, CHAr), 8.50 (dd, 4J = 4.5,

4J = 1.3 Hz, 1H, CHAr), 8.25 – 8.03 (m, 3H, CHAr), 7.91 (dd, 3J = 10.3, 4J = 2.7 Hz, 1H, CHAr),

7.52 (dd, 3J = 6.0, 4J = 3.3 Hz, 2H, CHAr), 7.41 – 7.26 (m, 2H, CHAr), 7.11 (s, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ = -118.48.

13C NMR (63 MHz, CDCl3) δ = 159.3 (d, 1J = 242.1 Hz, CF), 142.1 (CHAr), 134.6, 131.9, 130.4

(CAr), 128.9, 128.7, 128.4 (CHAr), 126.8 (d, 4J = 1.9 Hz, CAr), 125.8 (CAr), 124.3 (CHAr), 123.4

(d, 3J = 7.6 Hz, CAr), 122.9 (CHAr), 122.2 (CAr), 121.0 (d, 3J = 7.8 Hz, CHAr), 117.9 (CHAr),

116.4 (d, 2J = 22.4 Hz, CHAr), 109.3 (d, 2J = 24.0 Hz, CHAr), 93.0 (CHAr).

MS (EI, 70 eV): m/z(%) = 286 (M+, 100), 258 (10), 232 (3), 143 (17), 129 (4), 115 (3).

APPENDIX

xxxvii

HRMS (EI): calculated for C19H11N2F1 (M+): 286.09008, found: 286.08990.

6-(Methylthio)pyrido[3',2':4,5]pyrrolo[1,2-f]phenanthridine 3.9c


IR (ATR, cm-1): = 3107.2 (w), 3037.2 (w), 2918.0 (w), 2849.6 (w),

2731.2 (w), 2520.1 8w), 2387.1 (w), 2116.4 (w), 1959.0 (w), 1916.1 (w),

1724.9 (w), 1595.9 (m), 1541.6 (m), 1453.3 (s), 1405.6 (s), 1323.5 (m),

1103.3 (m), 955.8 (m), 818.2 (m), 793.9 (s), 758.7 (s), 730.2 (s), 646.5

(m), 585.3 (m).

1H NMR (300 MHz, CDCl3) δ = 10.14 (d, 3J = 8.9 Hz, 1H, CHAr), 8.49 (dd, 4J = 4.6,

4J = 1.7 Hz, 1H, CHAr), 8.27 – 8.11 (m, 2H, CHAr), 8.10 – 7.99 (m, 2H, CHAr), 7.57 – 7.41 (m,

3H, CHAr), 7.26 (dd, 3J = 7.9, 4J = 4.7 Hz, 1H, CHAr), 7.06 (s, 1H, CHAr), 2.61 (s, 3H, SCH3).

13C NMR (75 MHz, CDCl3) δ = 147.1 (CAr), 142.0 (CHAr), 134.7, 133.4, 132.9 (CAr), 128.5 (2

CHAr), 128.4, 128.2 (CHAr), 127.0, 125.7 (CAr), 124.2, 122.7 (CHAr), 122.3 (CAr), 122.2 (CHAr),

122.0 (CAr), 119.8, 117.7, 93.0 (CHAr), 17.2 (SCH3).

MS (EI, 70 eV): m/z(%) = 314 (M+, 100), 299 (59), 266 (7), 255 (29), 227 (3), 201 (1), 157

(14), 133 (5), 113 (2).

HRMS (EI): calculated for C20H14N2S1 (M+): 314.08722, found: 314.08645.

General procedure for domino reaction of dibromide compounds and

N-tosylhydrazones

Dibromide compound 4.1 (0.2 mmol), N-tosylhydrazone 4.2 (1.5 equiv., 0.3 mmol),

Pd2(dba)3 (2.5 mol%, 4.6 mg, 0.005 mmol), XPhos (10 mol%, 9.6 mg, 0.01 mmol), and LiOtBu

(4 equiv. 64 mg, 0.8 mmol) were placed in a dried pressure tube equipped with a septum. The

reaction vessel was back-filled with argon three times. Then dried and degassed dioxane (4 mL)

was added to the reaction mixture under argon and the septum was replaced with a Teflon cap.

The reaction mixture was stirred at 20 °C for 15 mins and then at 90 °C for 4 hours. After

cooling to room temperature, water (10 mL) and ethyl acetate (10 mL) were added and the

organic layer was separated. The aqueous layer was extracted three times with ethyl acetate

(3x10 mL). Combined organic layers were dried over MgSO4 and the solvent was removed

under reduced pressure. The residue was chromatographed (silica gel, heptane) to obtain the

pure product.

5-Phenylbenzo[b]naphtho[2,1-d]thiophene 4.3a

APPENDIX

xxxviii

White solid, 83% (52 mg). M.p.: 196–197 °C.

IR (ATR, cm-1): 3041.6 (w), 1950.5 (w), 1893.8 (w), 1802.3 (w), 1745.3

(w), 1432.7 (w), 1339.2 (w), 1247.1 (w), 1155.1 (w), 1071.7 (w), 873.6

(m), 744.8 (s), 697.5 (s).

1H NMR (250 MHz, CDCl3) δ 8.27 – 8.15 (m, 2H, CHAr), 8.13 (s, 1H, CHAr), 8.06 – 7.92 (m,

2H, CHAr), 7.71 – 7.44 (m, 9H, CHAr).

13C NMR (63 MHz, CDCl3) δ 140.9, 139.4, 138.2, 137.0, 136.8, 132.3, 131.1 (CAr), 130.5 (2

CHAr), 129.3 (CAr), 128.5 (2CHAr), 127.6 (2CHAr), 126.8, 126.5, 126.4, 124.9, 124.8, 123.1,

121.8, 120.7 (CHAr).

MS (EI, 70 eV): m/z (%) = 310 (M+, 100), 276 (4), 154 (28), 131 (7), 118 (4).

HRMS (EI): Calculated for C22H14S1 (M+): 310.08107, found: 310.08151.

5-(p-Tolyl)benzo[b]naphtho[2,1-d]thiophene 4.3b


IR (ATR, cm-1): 3043.5 (w), 2919.8 (w), 2860.6 (w), 2726.5 (w), 1895.5

(w), 1512.0 (w), 1433.0 (w), 1339.7 (w), 1107.1 (w), 875.8 (m), 819.9

(m), 747.0 (s), 607.2 (m).

1H NMR (300 MHz, CDCl3) δ 8.24 – 8.16 (m, 2H, CHAr), 8.13 (s, 1H,


7.56 – 7.46 (m, 5H, CHAr), 7.38 (d, 3J = 7.8 Hz, 2H, CHAr), 2.52 (s, 3H, CH3).

13C NMR (75 MHz, CDCl3) δ 139.4, 138.1, 138.0, 137.3, 136.8, 132.3, 131.2 (CAr), 130.3

(2CHAr), 129.3 (CAr), 129.2 (2CHAr), 127.6, 126.7, 126.4, 126.3, 124.9, 124.7, 123.1, 121.7,

120.7 (CHAr), 21.4 (CH3) (signal of one tertiary carbon is overlapped).

MS (EI, 70 eV): m/z (%) = 324 (M+, 100), 308 (36), 154 (10), 125 (2), 39 (7).


5-(4-(Trifluoromethyl)phenyl)benzo[b]naphtho[2,1-d]thiophene 4.3c

Yellowish solid, 53% (40 mg). M.p.: 167–169 °C.

IR (ATR, cm-1): 3066.7 (w), 2922.7 (w), 2851.0 (w), 1923.3 (w),

1724.8 (w), 1614.7 (m), 1435.9 (m), 1319.7 (s), 1159.9 (s), 1102.4 (s),

1063.7 (s), 841.6 (m), 749.9 (s), 632.4 (m).

APPENDIX

xxxix


8.04 – 7.95 (m, 1H, CHAr), 7.89 (dd, 3J = 7.2, 3J = 6.8 Hz, 1H, CHAr), 7.85 – 7.77 (m, 2H,

CHAr), 7.75 – 7.61 (m, 3H, CHAr), 7.61 – 7.46 (m, 3H, CHAr).

19F NMR (282 MHz, CDCl3) δ -62.62.

13C NMR (75 MHz, CDCl3) δ 144.7, 139.4, 137.8, 136.6, 136.5, 132.2 (CAr), 130.8 (2CHAr),

130.6 (CAr), 129.8 (q, 2J = 32.5 Hz, C-CF3), 129.3 (CAr), 127.1, 127.0, 126.8, 126.6 (CHAr),

125.5 (q, 3J = 3.8 Hz, 2CHAr), 125.1, 124.9 (CHAr), 124.5 (q, 1J = 272.0 Hz, CF3), 123.2, 121.7,

120.9 (CHAr).

HRMS (EI): Calculated for C23H13F3S1 (M+): 378.06848, found: 378.06817.

4-(Benzo[b]naphtho[2,1-d]thiophen-5-yl)phenol 4.3d


IR (ATR, cm-1): 3534.5 (w), 3163.9 (w, br), 3040.1 (w), 2924.4 (w),

1888.9 (w), 1592.8 (m), 1506.0 (m), 1433.2 (m), 1339.9 (m), 1226.1 (s),

991.2 (m), 832.1 (s), 748.9 (s), 607.3 (m).



7.08 – 6.96 (m, 2H, CHAr), 4.90 (s, br, 1H, OH).


(2CHAr), 131.4, 129.3 (CAr), 127.6, 126.8, 126.5, 126.4, 125.0, 124.7, 123.1, 121.8, 120.7

(CHAr), 115.4 (2CHAr).

MS (EI, 70 eV): m/z (%) = 326 (M+, 100), 308 (9), 295 (17), 271 (4), 224 (2), 148 (18), 135

(6).

HRMS (EI): Calculated for C22H14O1S1 (M+): 326.07599, found: 326.07548.

4-(Benzo[b]naphtho[2,1-d]thiophen-5-yl)benzonitrile 4.3e


IR (ATR, cm-1): 3405.7 (w), 3046.0 (w), 3014.7 (w), 2223.6 (m), 1938.8

(w), 1602.3 (m), 1508.3 (m), 1341.4 (m), 989.5 (m), 836.7 (m), 747.0

(s), 720.4 (m), 614.1 (m), 573.9 (m).

APPENDIX

xl


1H, CHAr), 7.92 – 7.78 (m, 3H, CHAr), 7.75 – 7.60 (m, 3H, CHAr), 7.60 – 7.45 (m, 3H, CHAr).

13C NMR (75 MHz, CDCl3) δ 145.7, 139.2, 138.0, 136.4, 135.9 (CAr), 132.2 (2CHAr), 132.0

(CAr), 131.0 (2CHAr), 130.1, 129.2 (CAr), 127.1, 126.9, 126.6, 126.5, 125.1, 124.8, 123.0, 121.6,

120.7 (CHAr), 118.9 (CN), 111.3 (CAr).

MS (EI, 70 eV): m/z (%) = 335 (M+, 100), 167 (15), 153 (14), 131 (9).

HRMS (EI): Calculated for C23H13N1S1 (M+): 335.07632, found: 335.07571.

5-(4-Fluorophenyl)benzo[b]naphtho[2,1-d]thiophene 4.3f


IR (ATR, cm-1): 3063.9 (w), 2926.3 (w), 1889.9 (w), 1667.1 (w), 1597.5

(m), 1504.2 (m), 1434.1 (m), 1215.5 (m), 1153.0 (m), 1089.1 (m), 876.9

(m), 835.6 (m), 749.0 (s), 605.1 (m).



7.33 – 7.17 (m, 2H, CHAr).

19F NMR (235 MHz, CDCl3) δ -115.13.


4J = 3.4 Hz, CAr), 136.7, 132.2 (CAr), 132.0 (d, 3J = 8.0 Hz, 2CHAr), 131.1, 129.3 (CAr), 127.3,

126.9, 126.6, 126.5, 125.0, 124.8, 123.1, 121.7, 120.8, 115.5 (d, 2J = 21.3 Hz, 2CHAr).

MS (EI, 70 eV): m/z (%) = 328 (M+, 100), 163 (23), 154 (10), 140 (8).


5-(2-Fluorophenyl)benzo[b]naphtho[2,1-d]thiophene 4.3g


IR (ATR, cm-1): 3054.6 (w), 1693.9 (w), 1575.4 (w), 1488.7 (m), 1449.4

(w), 1339.4 (w), 1247.6 (w), 1210.9 (w), 1095.3 (w), 887.4 (m), 746.9

(s), 725.7 (m), 611.8 (m).



7.38 – 7.22 (m, 2H, CHAr).

19F NMR (235 MHz, CDCl3) δ -113.51.

APPENDIX

xli


4J = 3.4 Hz, CHAr), 132.2, 131.7, 131.1 (CAr), 129.8 (d, 3J = 8.0 Hz, CHAr), 129.2, 128.2 (d,

2J = 16.3 Hz, CAr), 127.3 (d, 4J = 1.2 Hz, CHAr), 126.9, 126.7, 126.5, 125.0, 124.8 (CHAr), 124.4

(d, 3J = 3.6 Hz, CHAr), 123.1, 121.8, 121.6, 115.9 (d, 2J = 22.2 Hz, CHAr).

MS (EI, 70 eV): m/z (%) = 328 (M+, 100), 163 (23), 154 (11), 131(5).


4-(Benzo[b]naphtho[2,1-d]thiophen-5-yl)pyridine 4.3h


IR (ATR, cm-1): 3066.6 (w), 3022.5 (w), 2922.7 (w), 1935.3 (w), 1693.5

(w), 1591.4 (m), 1402.2 (m), 1340.3 (w), 1062.1 (w), 988.3 (w), 823.4

(m), 749.2 (s), 726.3 (s), 617.4 (m).

1H NMR (300 MHz, CDCl3) δ 8.85 (s, br, 2H, CHAr), 8.26 – 8.16 (m, 2H,

CHAr), 8.10 (s, 1H, CHAr), 8.03 – 7.96 (m, 1H, CHAr), 7.93 (d, 3J = 8.2 Hz, 1H, CHAr),

7.73 – 7.43 (m, 6H, CHAr).

13C NMR (75 MHz, CDCl3) δ 149.6, 139.3, 138.4, 136.5, 135.1, 132.2, 129.9, 129.4 (CAr),

127.3, 127.1, 126.7, 126.7, 125.2, 124.9, 123.2, 121.7, 120.7 (CHAr). (signals of 4CHAr could

not be detected).

MS (EI, 70 eV): m/z (%) = 311 (M+, 100), 282 (12), 155 (23), 141 (14), 107 (4). HRMS (EI):

Calculated for C21H13N1S1 (M+): 311.07632, found: 311.07582.

5-(4-Methoxyphenyl)benzo[b]naphtho[2,1-d]thiophene 4.3i


IR (ATR, cm-1): 3043.2 (w), 2947.3 (w), 2832.6 (w), 1604.6 (m),

1509.9 (m), 1432.5 (m), 1290.1 (w), 1240.1 (m), 1168.9 (m), 1031.0

(m), 875.6 (m), 829.8 (m), 751.5 (s), 723.4 (,), 606.7 (m). 551.1 (m).



7.16 – 7.05 (m, 2H, CHAr), 3.94 (s, 3H, OCH3).


(2CHAr), 131.4, 129.3 (CAr), 127.6, 126.7, 126.4, 126.4, 124.9, 124.7, 123.1, 121.7, 120.7

(CHAr), 113.9 (2CHAr), 55.5 (OCH3).

APPENDIX

xlii

MS (EI, 70 eV): m/z (%) = 340 (M+, 100), 325 (26), 295 (36), 269 (3), 148 (26), 135 (9).


5-(3-Methoxyphenyl)benzo[b]naphtho[2,1-d]thiophene 4.3j


IR (ATR, cm-1): 3047.3 (w), 2960.5 (w), 2831.0 (w), 1705.6 (w), 1582,9

(m), 1485.3 (m), 1459.4 (m), 1255.7 (m), 1214.0 (m), 1077.1 (m), 1034.1

(m), 952,2 (m), 789.8 (s), 748.3 (s), 649.4 (m), 570.3 (m).


CHAr), 8.07 – 7.90 (m, 2H, CHAr), 7.68-7.59 (m, 1H, CHAr), 7.58 – 7.41 (m, 4H, CHAr),

7.22 – 7.10 (m, 2H, CHAr), 7.09-7.00 (m, 1H, CHAr), 3.90 (s, 3H, OCH3).


129.5 (CHAr), 129.3 (CAr), 127.6, 126.8, 126.5, 126.4, 124.9, 124.8, 123.1, 123.0, 121.8, 120.6,

116.1, 113.1 (CHAr), 55.5 (OCH3).

MS (EI, 70 eV): m/z (%) = 340 (M+, 100), 325 (3), 308 (10), 295 (33), 148 (22), 135 (8).


5-(2-Methoxyphenyl)benzo[b]naphtho[2,1-d]thiophene 4.3k


IR (ATR, cm-1): 3064.5 (w), 2952.0 (w), 2834.7 (w), 1578.4 (w), 1491.1

(m), 1461.4 (m), 1432.8 (m), 1339.4 (w), 1289.0 (m), 1241.1 (m), 1111.2

(m), 1024.2 (m), 875.4 (m), 746.2 (s), 724.4 (m), 614.1 (m), 551.5 (m).


1H, CHAr), 7.69 (d, 3J = 8.4 Hz, 1H, CHAr), 7.64-7.56 (m, 1H, CHAr), 7.55 – 7.43 (m, 4H,

CHAr), 7.40 (dd, 3J = 7.4, 4J = 1.7 Hz, 1H, CHAr), 7.19 – 7.05 (m, 2H, CHAr), 3.72 (s, 3H,

OCH3).

13C NMR (63 MHz, CDCl3) δ 157.6, 139.3, 137.1, 136.9, 134.9, 132.4 (CAr), 132.3 (CHAr),

131.6, 129.7 (CAr), 129.4 (CHAr), 129.0 (CAr), 127.9, 126.6, 126.3, 126.2, 124.8, 124.6, 123.1,

121.8, 121.1, 120.9, 111.2 (CHAr), 55.7 (OCH3).

MS (EI, 70 eV): m/z (%) = 340 (M+, 100), 324 (21), 308 (5), 297 (28), 265 (4), 148 (21), 135

(9).

APPENDIX

xliii


5-(Naphthalen-1-yl)benzo[b]naphtho[2,1-d]thiophene 4.3l

White solid, 65% (47 mg). M.p.: 217–218 °C

IR (ATR, cm-1): 3043.8 (w), 2952.5 (w), 2850.6 (w), 1921.1 (w), 1506.2

(w), 1432.7 (m), 1235.3 (w), 1102.5 (w), 1018.6 (m), 879.7 (m), 798.7

(m), 772.9 (s), 748.4 (s), 725.4 (s), 698.6 (m), 600.2 (m), 578.3 (m).



7.55 – 7.43 (m, 5H, CHAr), 7.43 – 7.27 (m, 2H, CHAr).

13C NMR (75 MHz, CDCl3) δ 139.4, 138.5, 137.3, 136.8, 136.3, 133.7, 133.2, 132.4, 132.2,

129.1 (CAr), 128.4, 128.3, 128.3, 128.0, 126.9, 126.8, 126.5, 126.5, 126.3, 126.1, 125.6, 124.9,

124.8, 123.2, 121.8, 121.7 (CHAr).

MS (EI, 70 eV): m/z (%) = 360 (M+, 100), 179 (46), 120 (3).


5-(Naphthalen-2-yl)benzo[b]naphtho[2,1-d]thiophene 4.3m


IR (ATR, cm-1): 3036.6 (w), 2919.9 (w), 2849.9 (w), 1920.8 (w),

1704.2 (w), 1596.4 (w), 1434.9 (w), 1240.1 (w), 962.3 (m), 858.5

(m), 815.7 (m), 747.2 (s), 726.9 (s), 669.6 (m), 627.2 (m).


(m, 6H, CHAr), 7.75 – 7.47 (m, 7H, CHAr).

13C NMR (63 MHz, CDCl3) δ 139.4, 138.5, 138.1, 137.2, 136.8, 133.6, 132.8, 132.4, 131.3,

129.4 (CAr), 129.1, 128.8, 128.2, 127.9, 127.9, 127.6, 126.9 (CHAr), 126.6 (2CHAr), 126.5,

126.3, 125.0, 124.8, 123.1, 121.8, 121.1 (CHAr).

MS (EI, 70 eV): m/z (%) = 360 (M+, 100), 179 (43), 143 (4).


5-([1,1'-Biphenyl]-4-yl)benzo[b]naphtho[2,1-d]thiophene 4.3n

APPENDIX

xliv


IR (ATR, cm-1): 3031.2 (w), 1599.4 (w), 1487.9 (w), 1433.1 (w), 1339.8

(w), 1235.3 (w), 990.0 (w), 888.3 (w), 842.8 (m), 747.0 (s), 724.2 (s),

693.0 (m), 645.3 (m), 579.8 (m).



7.60 – 7.46 (m, 5H, CHAr), 7.46 – 7.37 (m, 1H, CHAr).

13C NMR (63 MHz, CDCl3) δ 140.9, 140.5, 139.9, 139.4, 137.7, 137.1, 136.8, 132.3, 131.1

(CAr), 130.9 (2CHAr), 129.4 (CAr), 129.0 (2CHAr), 127.6, 127.6 (CHAr), 127.3 (2CHAr), 127.2

(2CHAr), 126.9, 126.6, 126.4, 125.0, 124.8, 123.1, 121.8, 120.8 (CHAr).

MS (EI, 70 eV): m/z (%) = 386 (M+, 100), 308 (20), 193 (10), 154 (6), 77 (5).


6-Phenylbenzo[b]benzo[4,5]thio[3,2-g]benzothiophene 4.3o

Yellow, 34% (25 mg). M.p.: 230–231 °C.

IR (ATR, cm-1): 3054.1 (w), 3025.7 (w), 2920.0 (w), 2849.8 (w),

1942.8 (w), 1905.1 (w), 1820.8 (w), 1788.0 (w), 1750.0 (w), 1693.4

(w), 1600.7 (w), 1435.4 (w), 1405.1 (m), 1330.9 (m), 1231.1(m),

1157.7 (m), 1111.9 (m), 876.9 (m), 755.7 (s), 728.2 (s), 699.6 (s),

646.1 (m), 568.9 (m).



7.42 – 7.33 (m, 1H, CHAr), 7.20 – 7.07 (m, 2H, CHAr).

13C NMR (63 MHz, CDCl3) δ 141.5, 139.7, 139.4, 136.5, 136.2, 136.1, 133.8, 133.7, 132.4,

132.0 (CAr), 129.6 (2CHAr), 128.9 (2CHAr), 128.1, 127.0, 126.3, 125.1, 125.0, 124.4, 123.2,

123.0, 122.2, 120.4 (CHAr).

MS (EI, 70 eV): m/z (%) = 366 (M+, 100), 332 (5), 182 (30), 160 (6), 121 (2).

HR-MS(+ESI): calculated for C24H15S2 (M+H)+: 367.06097, found: 367.06144.

5-Phenylnaphtho[1,2-b]benzofuran 4.5a

APPENDIX

xlv


IR (ATR, cm-1): 3030.2 (w), 2922.0 (w), 2850.8 (w), 1892.7 (w), 1576.1

(w), 1493.1 (w), 1457.9 (m), 1440.5 (m), 1403.5 (m), 1355.6 (m), 1235.5

(m), 1192.5 (m), 1171.9 (m), 1048.3 (m), 883.3 (m), 787.1 (m), 769.4

(m), 741.9 (s), 697.9 (s), 603.0 (m), 582.5 (m).

1H NMR (300 MHz, CDCl3) δ 8.54 (dd, 3J = 8.2, 5J = 0.5 Hz, 1H, CHAr), 8.00 (d, 3J = 8.2 Hz,

2H, CHAr), 7.96 (s, 1H, CHAr), 7.75 (d, 3J = 8.2 Hz, 1H, CHAr), 7.71-7.63 (m, 1H, CHAr),

7.61 – 7.37 (m, 8H, CHAr).


(2CHAr), 127.4, 127.2, 126.5, 126.5, 126.3 (CHAr), 125.2 (CAr), 123.2 (CHAr), 121.7 (CAr),

121.3, 120.4, 119.5, 118.8 (CAr), 112.0 (CHAr).

MS (EI, 70 eV): m/z (%) = 294 (M+, 100), 263 (15), 239 (4), 146 (8), 132 (15), 119 (10).

HRMS (EI): Calculated for C22H14O1 (M+): 294.10392, found: 294.10358.

5-(p-Tolyl)naphtho[1,2-b]benzofuran 4.5b


IR (ATR, cm-1): 3025.9 (w), 2917.4 (w), 2863.5 (w), 2731.7 (w), 1930.0

(w), 1814.0 (w), 1634.2 (w), 1577.5 (w), 1459.1 (m), 1351.9 (m),

1236.6 (w), 1195.9 (m), 1049.3 (m), 822.6 (m), 766.1 (m), 739.8 (s),

601.2 (m).


1H, CHAr), 7.81 – 7.60 (m, 2H, CHAr), 7.58 – 7.30 (m, 7H, CHAr), 2.51 (s, 3H, CH3).


129.2 (2CHAr), 127.3, 126.4, 126.4, 126.2 (CHAr), 125.3 (CAr), 123.1 (CHAr), 121.7 (CAr), 121.2,

120.4, 119.4 (CHAr), 118.8 (CAr), 112.0 (CHAr), 21.4 (CH3).

MS (EI, 70 eV): m/z (%) = 308 (M+, 100), 292 (10), 279 (6), 263 (5), 250 (5), 207 (10), 187

(4), 154 (8), 132 (11).


5-(4-Methoxyphenyl)naphtho[1,2-b]benzofuran 4.5c

APPENDIX

xlvi


IR (ATR, cm-1): 3019.8 (w), 2958.7 (w), 2906.4 (w), 2542.6 (w),

2351.3 (w), 2051.5 (w), 1923.9 (w), 1605.3 (m), 1509.4 (m), 1460.4

(m), 1355.7 (m), 1238.0 (m), 1104.2 (m), 1031.5 (m), 827.2 (m), 768.5

(m), 745.5 (s), 686.4 (m), 601.3 (m), 555.4 (m).


1H), 7.79 – 7.60 (m, 2H, CHAr), 7.60 – 7.34 (m, 5H, CHAr), 7.17 – 7.00 (m, 2H, CHAr), 3.93 (s,

3H, OCH3).

13C NMR (63 MHz, CDCl3) δ 159.1 (C-OCH3), 156.3, 151.7, 135.8, 133.4, 131.8 (CAr), 131.6

(2CHAr), 127.2, 126.4, 126.4, 126.2 (CHAr), 125.3 (CAr), 123.1 (CHAr), 121.7 (CAr), 121.2,

120.4, 119.4 (CHAr), 118.8 (CAr), 113.9 (2CHAr), 112.0 (CHAr), 55.5 (OCH3).

MS (EI, 70 eV): m/z (%) = 324 (M+, 100), 309 (31), 279 (21), 252 (17), 226 (5), 162 (8), 140

(7), 113 (10).


5-([1,1'-Biphenyl]-4-yl)naphtho[1,2-b]benzofuran 4.5d


IR (ATR, cm-1): 3029.6 (w), 2922.4 (w), 2850.5 (w), 1927.1 (w), 1580.5

(w), 1487.1 (m), 1440.6 (m), 1352.2 (m), 1236.5 (w), 1177.3 (m), 1049.4

(m), 838.7 (m), 763.6 (m), 741.9 (s), 692.7 (s), 606.2 (m), 587.4 (m).

1H NMR (300 MHz, CDCl3) δ 8.60 – 8.53 (m, 1H, CHAr), 8.09 (d,

3J = 8.5 Hz, 1H, CHAr), 8.05 – 7.97 (m, 2H, CHAr), 7.82 – 7.70 (m, 5H, CHAr), 7.70 – 7.62 (m,

3H, CHAr), 7.59 – 7.47 (m, 4H, CHAr), 7.47 – 7.36 (m, 2H, CHAr).


(2CHAr), 129.0 (2CHAr), 127.5 (CHAr), 127.3 (2CHAr), 127.2 (3CHAr), 126.6, 126.5, 126.3

(CHAr), 125.2 (CAr), 123.2 (CHAr), 121.7 (CAr), 121.3, 120.4, 119.6 (CHAr), 118.8 (CAr), 112.0

(CHAr).

MS (EI, 70 eV): m/z (%) = 370 (M+, 100), 339 (4), 292 (13), 263 (6) CHAr, 185 (8), 169 (7).


11-Methyl-5-phenyl-11H-benzo[a]carbazole 4.6a

APPENDIX

xlvii

Yellowish solid, 31% (19 mg). M. p.: 153–154 °C.

IR (ATR, cm-1): 3079.1 (w), 3055.4 (w), 3026.2 (w), 2918.9 (w), 1597.8

(w), 1518.4 (w), 1448.8 (m), 1334.5 (m), 1263.1 (m), 1133.2 (m), 1017.0

(m), 882.1 (m), 769.2 (m), 735.3 (s), 699.5 (s), 578.3 (s).

1H NMR (250 MHz, CDCl3) δ 8.81 (d, 3J = 8.1 Hz, 1H, CHAr),

8.17 – 8.04 (m, 3H, CHAr), 7.66 – 7.43 (m, 9H, CHAr), 7.35 – 7.27 (m, 1H, CHAr), 4.47 (s, 3H,

NCH3).


(2CHAr), 127.9, 127.0, 125.2, 125.0, 124.8 (CHAr), 123.2, 123.0 (CAr), 122.4, 120.4, 119.8,

119.8 (CHAr), 118.6 (CAr), 109.2 (CHAr), 34.4 (NCH3).

MS (EI, 70 eV): m/z (%) = 307 (M+, 100), 291 (35), 152 (12), 146 (23), 131 (5), 118 (3).

HRMS (EI): Calculated for C23H17N1 (M+): 307.13555, found: 307.13495.

5-(4-Methoxyphenyl)-11-methyl-11H-benzo[a]carbazole 4.6b


IR (ATR, cm-1): 3119.2 (w), 3029.2 (w), 2956.9 (w), 2836.1 (w),

1926.1 (w), 1766.2 (w), 1658.8 (w), 1606.6 (m), 1572.5 (m), 1508.6

(s), 1440.4 (s), 1335.6 (m), 1233.7 (s), 1169.8 (s), 1103.7 (m), 1027.6

(s), 884.2 (m), 835.5 (s), 738.4 (s), 690.2 (m), 547.7 (s).



(m, 2H, CHAr), 4.44 (s, 3H, NCH3), 3.93 (s, 3H, OCH3).


127.9, 125.1, 124.9, 124.7 (CHAr), 123.2, 123.0 (CAr), 122.4, 120.4, 119.8, 119.7 (CHAr), 118.6

(CAr), 113.9 (2CHAr), 109.2 (CHAr), 55.5 (OCH3), 34.3 (NCH3).

MS (EI, 70 eV): m/z (%) = 337 (M+, 100), 322 (37), 278 (27), 168 (10), 145 (20).

HRMS (EI): Calculated for C24H19O1N1 (M+): 337.14612, found: 337.14559.

5-([1,1'-Biphenyl]-4-yl)-11-methyl-11H-benzo[a]carbazole 4.6c

APPENDIX

xlviii


IR (ATR, cm-1): 3056.4 (w), 3026.0 (w), 1594.1 (w), 1516.7 (w), 1464.9

(w), 1375.0 (w), 1334.9 (w), 1264.7 (w), 1227.0 (w), 1062.7 (w), 897.7

(m), 845.0 (m), 770.6 (m), 726.0 (s), 693.7 (s), 637.5 (m), 583.0 (m).


8.25 – 8.11 (m, 3H, CHAr), 7.85 – 7.45 (m, 12H, CHAr), 7.45 – 7.29 (m,

2H, CHAr), 4.47 (s, 3H, NCH3).


(2CHAr), 129.0 (2CHAr), 127.9, 127.4 (CHAr ), 127.3 (2CHAr), 127.2 (2CHAr), 125.3, 125.1,

124.9 (CHAr), 123.2, 123.1 (CAr), 122.4, 120.5, 119.8, 119.8 (CHAr), 118.6 (CAr), 109.2 (CHAr),

34.4 (NCH3).

MS (EI, 70 eV): m/z (%) = 383 (M+, 100), 367 (14), 341 (1), 291 (10), 184 (9), 152 (4), 77 (4).

HRMS (EI): Calculated for C29H21N1 (M+): 383.16685, found 383.16645.

2-(2-Chlorophenyl)-3-(1-phenylvinyl)benzo[b]thiophene 4.4

Yellowish oil.

IR (ATR, cm-1):3054.8 (w), 3023.3 (w), 1609.9 (m), 1491.6 (m), 1430.9

(m), 1241.0 (w), 1059.9 (m), 1026.7 (w), 904.5 (m), 777.9 (m), 748.6

(s), 732.2 (s), 701.8 (s), 597.7 (m).


(m, 1H, CHAr), 7.45 – 7.34 (m, 5H, CHAr), 7.34 – 7.13 (m, 6H, CHAr), 5.82 (d, 2J = 1.3 Hz, 1H,

C=CH2), 5.34 (d, 2J = 1.3 Hz, 1H, C=CH2).


132.8, 129.8, 129.7 (CHAr), 128.3 (2CHAr), 127.8 (CHAr), 126.9 (2CHAr), 126.4, 124.7, 124.4,

124.2, 122.2 (CHAr), 118.1 (C=CH2).

MS (EI, 70 eV): m/z (%) = 346 (M+, 16), 311 (100), 295 (7), 269 (6), 234 (38), 189 (8), 154

(16), 77 (7).

HRMS (EI): Calculated for C22H1535Cl1S1 (M

+): 346.05775, found: 346.05749.

General procedure for the synthesis of pyrazoles

Acetophenone 5.1 (0.5 mmol, 1 eq) and phenylhydrazine (0.525 mmol, 1.05 eq) were

dissolved in 2 mL of DCM. The solution was stirred for 1 min at room temperature and then

APPENDIX

xlix

the solvent was removed under reduced pressure. The residue was stirred at room temperature

and 3 drops of acetic acid were added. The reaction mixture was stirred for 5 min to complete

the reaction. (In most cases, the product was solid and the reaction mixture became solid as the

reaction completed). The reaction carried out nearly qualitative. Then the crude product was

dissolved in 10 mL of DCM. After that, solvent, water, and acetic acid were removed under

reduced pressure and the product was transferred to the next step without further purification.

To a solution of hyrazone 5.2 (0.5 mmol) in 7 mL of dry THF was added n-butyllithium

(0.44 mL, 2.2 equiv., 2.5 M solution in hexane) slowly at -78 °C under Ar. After adding n-

-butyllithium, the mixture was allowed to warm to 20 °C and stirred at that temperature for 15

min. Then the reaction was cooled to -78 °C again and ethyl perfluorocarboxylate 5.3 (1.5 eq,

solution in 1 mL THF) was added at this temperature. The reaction was allowed to warm to

20 °C and stirred for 30 min, subsequently, 1 mL of TFA was added. The mixture was stirred

under reflux for 2 h. After cooling, a saturated aqueous solution of NaHCO3 was added until no

CO2 evolution was observed. Then THF was removed and the remained water was extracted

with ethyl acetate (10 mL 3x). Combined organic layers were dried over MgSO4 and the solvent

was removed under reduced pressure. The residue was purified by chromatography (silica gel,

n-heptane/DCM).

1,3-Diphenyl-5-(trifluoromethyl)-1H-pyrazole 5.4a


IR (ATR, cm-1): ν = 549 (s), 615 (m), 685 (s), 760 (s), 773 (s), 812 (s),

956 (m), 9872 (s), 1028 (s), 1072 (s), 1118 (s), 1138 (m), 1211 (s), 1232

(s), 1288 (s), 1363 (m), 1444 (s), 1502 (m), 1556 (m), 1593 (m), 3054 (w), 3070 (w), 3139 (w).

1H NMR (300 MHz, CDCl3) δ 7.92 – 7.83 (m, 2H, CHPh), 7.65 – 7.32 (m, 8H, CHPh), 7.12 (s,

1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -57.59.

13C NMR (75 MHz, CDCl3) δ 151.8, 139.3 (CAr), 134.0 (q, 2J = 39.2 Hz, C-CF3), 131.9 (CAr),

129.4 (CHAr), 129.26 (2CHAr), 128.9 (2CHAr), 128.8 (CHAr), 126.0 (2CHAr), 125.9, 125.9

(CHAr), 119.9 (q, 1J = 269.2 Hz, CF3), 106.2 (q, 3J = 2.4 Hz, CHHetAr).

GC-MS (EI, 70 eV): m/z (%) = 288 (100), 267 (37), 219 (9), 77 (20).

HRMS (EI): calcd. for C16H11F3N2 ([M]+): 288.08688, found: 288.08678.

3-(4-Methoxyphenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole 5.4b

APPENDIX

l

Yellow solid, 79% (127 mg). M.p.: 77–78 °C.

IR (ATR, cm-1): ν = 548 (m), 617 (m), 685 (s), 767 (s), 810 (s),

833 (m), 956 (m), 987 (s), 1031 (s), 1080 (s), 1088 (s), 1115 (s),

1151 (s), 1209 (s), 1248 (s), 1290 (s), 1359 (w), 1435 (s), 1450 (s), 1502 (s), 1558 (m), 1595

(m), 1614 (m), 2845 (w), 2943 (w), 2970 (w), 3022 (w), 3068 (w), 3130 (w).


1H, CHAr), 7.02 – 6.90 (m, 2H, CHAr), 3.85 (s, 3H, OCH3).

19F NMR (282 MHz, CDCl3) δ -57.59.

13C NMR (75 MHz, CDCl3) δ 160.2, 151.6, 139.4 (CAr), 133.9 (q, 2J = 39.0 Hz, C-CF3), 129.3

(CHAr), 129.2 (2CHAr), 127.3 (2CHAr), 125.9, 125.9 (CHAr), 124.5 (CAr), 119.9 (q,

1J = 269.1 Hz, CF3), 114.3 (2CHAr), 105.8 (q, 3J = 2.4 Hz, CHHetAr), 55.47 (OCH3).

GC-MS (EI, 70 eV): m/z (%) = 318 (100), 303 (26), 275 (12), 77 (12).

HRMS (EI): calcd. for C17H13F3N2O ([M]+): 318.09745, found: 318.09788.

3-(3-Methoxyphenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole 5.4c

Pale yellow oil, 81% (129 mg).

IR (ATR, cm-1): ν = 544 (m), 627 (m), 688 (s), 766 (s), 816 (m), 847

(m), 916 (w), 987 (s), 1041 (s), 1089 (s), 1124 (s), 1143 (s), 1197 (s),

1224 (s), 1257 (m), 1284 (m), 1354 (m), 1433 (s), 1464 (m), 1500 (s), 1556 (m), 1597 (m), 2835

(w), 2939 (w), 3003 (w), 3063 (w), 3138 (w).

1H NMR (300 MHz, CDCl3) δ 7.63 – 7.47 (m, 5H, CHAr), 7.47 – 7.40 (m, 2H, CHAr), 7.35 (t,

3J = 8.1 Hz, 1H, CHAr), 7.10 (s, 1H, CHAr, ), 6.93 (m, 1H, CHAr), 3.87 (s, 3H, OCH3).

19F NMR (282 MHz, CDCl3) δ -57.60.


(CAr), 130.0, 129.5 (CHAr), 129.3 (2CHAr), 125.9, 125.9 (CHAr), 119.9 (q, 1J = 269.2 Hz, CF3),

118.5, 114.8, 111.1 (CHAr), 106.4 (q, 3J = 2.4 Hz, CHHetAr), 55.5 (OCH3).

GC-MS (EI, 70 eV): m/z (%) = 318 (100), 297 (8), 267 (8), 205 (3), 77 (20). HRMS (EI): calcd.

for C17H13F3N2O ([M]+): 318.09745, found: 318.09718.

3-(2-Methoxyphenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole 5.4d

APPENDIX

li

Pale yellow solid, 61% (109 mg). M.p.: 70–71 °C.

IR (ATR, cm-1): ν = 542 (m), 692 (s), 750 (s), 777 (s), 814 (s), 989 (s),

1028 (s), 1068 (s), 1084 (s), 1113 (s), 1157 (s), 1201 (s), 1230 (s), 1246

(s), 1290 (s), 1354 (m), 1421 (m), 1437 (s), 1456 (m), 1473 (s), 1504 (m), 1556 (m), 1585 (m),

1595 (m), 2841 (w), 2943 (w), 3057 (w), 3180 (w).


CHAr), 7.41 – 7.30 (m, 2H, CHAr), 7.08 – 6.91 (m, 2H, CHAr), 3.96 (s, 3H, OCH3).

19F NMR (282 MHz, CDCl3) δ -57.38.

13C NMR (75 MHz, CDCl3) δ 156.9, 148.6, 139.4 (CAr), 132.9 (q, 2J = 39.0 Hz, C-CF3), 129.8,

129.1 (CHAr), 129.1 (2CHAr), 128.8, 125.8, 125.8, 120.9 (CHAr), 120.6 (CAr), 120.0 (q,

1J = 269.0 Hz, CF3), 111.3, 110.3 (q, 3J = 2.5 Hz, CHHetAr), 55.5 (OCH3).

GC-MS (EI, 70 eV): m/z (%) = 318 (100), 289 (64), 267 (27), 249 (28), 221 (14), 77 (60).


3-([1,1'-Biphenyl]-4-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole 5.4e


IR (ATR, cm-1): ν = 546 (m), 685 (s), 727 (s), 758 (s), 820 (s), 845

(m), 987 (s), 1086 (s), 1117 (s), 1149 (s), 1159 (s), 1201 (m), 1226

(s), 1290 (s), 1358 (m), 1410 (m), 1443 (s), 1502 (s), 1566 (w), 1595 (m), 2850 (w), 2920 (w),

3032 (w), 3053 (w), 3144 (w).


7.63 – 7.33 (m, 8H, CHAr), 7.16 (d, 5J = 0.3 Hz, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -57.57 (s).

13C NMR (75 MHz, CDCl3) δ 151.4, 141.5, 140.7, 139.4 (CAr), 134.1 (q, 2J = 39.2 Hz, C-CF3),

130.8 (CAr), 129.5 (CH), 129.3 (2CHAr), 128.9 (2CHAr), 127.6 (CHAr), 127.6 (2CHAr), 127.2

(2CHAr), 126.4 (2CHAr), 125.9, 125.9 (CHAr), 119.9 (q, 1J = 269.1 Hz, CF3), 106.3 (q,

3J = 2.4 Hz, CHHetAr).

GC-MS (EI, 70 eV): m/z (%) = 364 (100), 343 (11), 152 (10), 77(10).


1-Phenyl-3-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole 5.4f

APPENDIX

lii

Pale yellow solid, 87% (140 mg). M.p: 71–72 °C.

IR (ATR, cm-1): ν = 544 (m), 623 (m), 687 (s), 768 (s), 798 (s), 827

(m), 989 (s), 1086 (s), 1122 (s), 1155 (s), 1203 (m), 1232 (s), 1290

(m), 1440 (s), 1504 (m), 1556 (m), 1595 (w), 2357 (w), 2860 (w), 2922 (w), 3022 (w), 3061

(w).


7.33 – 7.18 (m, 2H, CHAr), 7.08 (s, 1H, CHAr), 2.40 (s, 3H, CH3).

19F NMR (282 MHz, CDCl3) δ -57.58.


(2CHAr), 129.4 (CHAr), 129.2 (2CHAr), 129.1 (CAr), 125.9 (4CHAr), 119.9 (q, 1J = 269.2 Hz,

CF3), 106.1 (q, 3J = 2.4 Hz, CHHetAr), 21.4 (CH3).

GC-MS (EI, 70 eV): m/z (%) = 302 (100), 281 (18), 267 (8), 233 (7), 77 (14).

HRMS (ESI): calcd. for C17H13F3N2 ([M+H]+): 303.11036, found: 303.11038.

3-(2-Fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole 5.4g

Pale yellow solid, 90% (138 mg). M.p. 73–74 °C.

IR (ATR, cm-1): ν = 553 (m), 625 (m), 661 (m), 686 (s), 750 (s), 771 (s),

820 (s), 833 (s), 947 (m), 960 (m), 989 (s), 1028 (m), 1070 (s), 1115 (s),

1165 (s), 1201 (s), 1238 (s), 1261 (m), 1290 (s), 1358 (m), 1423 (m), 1444 (s), 1471 (m), 1500

(m), 1554 (m), 1581 (m), 1587 (m), 1913 (w), 3056 (w), 3076 (w), 3165 (w).


7.50 – 7.35 (m, 1H, CHAr), 7.35 – 7.15 (m, 3H, CHAr).

19F NMR (282 MHz, CDCl3) δ -57.59, -116.00.

13C NMR (126 MHz, CDCl3) δ 160.5 (d, 1J = 250.0 Hz, CF), 146.5, 139.3 (CAr), 134.3 – 133.3

(m, 1C, CAr), 130.2 (d, 3J = 8.5 Hz, CHAr), 129.5 (CHAr), 129.3 (2CHAr), 128.6 (d, 3J = 11.5 Hz,

CHAr), 125.9, 125.9 (CHAr), 124.6 (d, 4J = 3.5 Hz, CHAr), 119.9 (q, 1J = 269.2 Hz, CF3), 119.9

(d, 2J = 20.8 Hz, CAr), 116.3 (d, 2J = 22.0 Hz, CHAr), 109.9-109.5 (m, 1C, CHHetAr).

GC-MS (EI, 70 eV): m/z (%) = 306 (100), 285 (38), 267 (9), 237 (7), 77 (15).

3-(4-Fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole 5.4h

APPENDIX

liii


IR (ATR, cm-1): ν = 544 (m), 619 (m), 692 (s), 750 (m), 769 (s), 808

(s), 837 (s), 956 (m), 987 (s), 1028 (m), 1066 (s), 1076 (s), 1086 (s),

1111 (s), 1155 (s), 1207 (s), 1228 (s), 1290 (s), 1440 (s), 1502 (s), 1525 (m), 1558 (m), 1595

(m), 1606 (m), 1888 (w), 3058 (w), 3141 (w).


7.20 – 7.07 (m, 2H, CHAr), 7.06 (s, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -57.65, -112.97.

13C NMR (75 MHz, CDCl3) δ 163.2 (d, 1J = 247.9 Hz, CF), 150.9, 139.3 (CAr), 134.2 (q,

2J = 39.2 Hz, C-CF3), 129.5 (CHAr), 129.3 (2CHAr), 128.1 (d, 4J = 3.2 Hz, CAr), 127.8 (d,

3J = 8.2 Hz, 2CHAr), 125.8, 125.8 (CHAr), 119.8 (q, 1J = 269.2 Hz, CF3), 115.9 (d, 2J = 21.8 Hz,

2CHAr), 106.0 (q, 3J = 2.4 Hz, CHHetAr).

GC-MS (EI, 70 eV): m/z (%) = 306 (100), 285 (40), 237 (9), 77 (17).


3-(Naphthalen-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole 5.4i


IR (ATR, cm-1): ν = 542 (m), 687 (s), 742 (s), 767 (s), 798 (s), 804

(s), 819 (m), 856 (s), 885 (m), 945 (m), 989 (s), 1028 (m), 1057 (s),

1074 (s), 1086 (s), 1113 (s), 1153 (s), 1230 (s), 1246 (s), 1290 (s), 1431 (m), 1485 (m), 1504

(s), 1556 (w), 1595 (m), 3028 (w), 3055 (w).

1H NMR (300 MHz, Acetone) δ 8.50 (s, 1H, CHAr), 8.13 (d, 3J = 8.3 Hz, 1H, CHAr), 8.04 – 7.88

(m, 3H, CHAr), 7.72 – 7.47 (m, 8H, CHAr).

19F NMR (282 MHz, Acetone) δ 119.44.

13C NMR (75 MHz, Acetone) δ 152.5, 140.4, 134.6, 134.6 (CAr), 134.5 (q, 2J = 39.0 Hz,

C-CF3), 130.6 (CAr), 130.3 (CHAr), 130.3 (2CHAr), 129.5, 129.3, 128.8, 127.6, 127.4, 126.9,

126.9, 125.7, 124.6 (CHAr), 121.1 (q, 1J = 268.4 Hz, CF3), 107.6 (q, 4J = 2.5 Hz, CHHetAr).

GC-MS (EI, 70 eV): m/z (%) = 338 (100), 317 (14), 127 (17), 77 (20).


1-Phenyl-5-(trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole 5.4j

APPENDIX

liv


IR (ATR, cm-1): ν = 552 (m), 592 (s), 625 (m), 687 (s), 766 (s), 804

(s), 845 (s), 991 (s), 1062 (s), 1068 (s), 1089 (s), 1093 (s), 1109 (s),

1132 (s), 1232 (s), 1288 (s), 1323 (s), 1419 (w), 1446 (m), 1504 (m), 1531 (w), 1558 (w), 1595

(m), 1622 (m), 3063 (w), 3145 (w).

1H NMR (300 MHz, CDCl3) δ 7.98 (d, 3J = 8.1 Hz, 2H, CHAr), 7.69 (d, 3J = 8.1 Hz, 2H, CHAr),

7.62 – 7.46 (m, 5H, CHAr), 7.16 (s, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -57.71, -62.63.

13C NMR (75 MHz, CDCl3) δ 150.3, 139.1 (CAr), 135.3 (d, 4J = 1.3 Hz, CAr), 134.5 (q,

2J = 39.6 Hz, C-CF3), 130.7 (q, 2J = 32.5 Hz, CAr), 129.7 (CHAr), 129.4 (2CHAr), 126.17

(2CHAr), 125.9 (q, 3J = 3.8 Hz, 2CHAr), 125.8 (q, 4J = 1.0 Hz, 2CHAr), 124.3 (q, 1J = 272.3 Hz,

CF3), 119.7 (q, 1J = 269.3 Hz, CF3), 106.5 (q, 3J = 2.4 Hz, CHHetAr).

GC-MS (EI, 70 eV): m/z (%) = 356 (100), 335 (51), 287 (10), 267 (10), 77 (27).


5-(Perfluoroethyl)-1,3-diphenyl-1H-pyrazole 5.4k.


IR (ATR, cm-1): ν = 544 (w), 580 (w), 602 (m), 619 (m), 630 (m), 688

(s), 711 (m), 750 (s), 765 (s), 777 (s), 814 (m), 914 (m), 937 (s), 958 (s),

1020 (m), 1041 (s), 1076 (m), 1092 (s), 1134 (s), 1190 (s), 1203 (s), 1223 (s), 1331 (m), 1444

(m), 1498 (m), 1595 (w), 3076 (w), 3151 (w).



19F NMR (282 MHz, CDCl3) δ -83.38 (t, 3JF-F = 2.9 Hz), -106.28 (q, 3JF-F = 2.9 Hz).

13C NMR (63 MHz, CDCl3) δ 152.1, 139.9 (CAr), 132.0 (t, 2J = 27.6 Hz, C-CF3), 131.7 (CAr),

129.7 (CHAr), 129.1 (2CHAr), 128.9 (2CHAr), 128.9 (CHAr), 126.9 (2CHAr), 126.0 (2CHAr),

107.4 – 107.0 (m, CHAr), signal of CF2CF3 could not be detected.

GC-MS (EI, 70 eV): m/z (%) = 338 (100), 319 (6), 269 (14), 219 (8), 77 (24).


3-(4-Methoxyphenyl)-5-(perfluoroethyl)-1-phenyl-1H-pyrazole 5.4l

APPENDIX

lv


IR (ATR, cm-1): ν = 532 (s), 576 (m), 602 (m), 617 (m), 634 (m),

694 (s), 748 (s), 771 (s), 804 (s), 835 (s), 935 (s), 958 (s), 1026

(s), 1036 (s), 1092 (s), 1134 (s), 1176 (s), 1190 (s), 1215 (s), 1250 (s), 1292 (m), 1331 (m),

1443 (m), 1502 (m), 1552 (w), 1596 (m), 1614 (m), 2839 (w), 2943 (w), 3010 (w), 3139 (w).


1H, CHAr), 7.00 – 6.92 (m, 2H, CHAr), 3.85 (s, 3H, CH3).


13C NMR (63 MHz, CDCl3) δ 160.2, 151.9, 139.9 (CAr), 131.9 (t, 2J = 27.6 Hz, C-CF3), 129.6

(CHAr), 129.0 (2CHAr), 127.3 (2CHAr), 126.9 (2CHAr), 124.5 (CAr), 114.3 (2 CHAr),

106.9 – 106.5 (m, CHAr), 55.5 (OCH3), signal of CF2CF3 could not be detected.

GC-MS (EI, 70 eV): m/z (%) = 368 (100), 353 (20), 77 (14).


3-(Naphthalen-2-yl)-5-(perfluoroethyl)-1-phenyl-1H-pyrazole 5.4m

Pale brown solid, 93% (181 mg). M.p.: 104–106 °C.

IR (ATR, cm-1): ν = 544 (w), 575 (m), 617 (m), 628 (m), 642 (m),

685 (s), 748 (s), 771 (s), 804 (s), 860 (s), 887 (m), 941 (s), 980 (m),

1020 (s), 1043 (s), 1095 (s), 1134 (s), 1190 (s), 1329 (m), 1431 (m), 1487 (m), 1504 (m),

1594.92 (m), 3043 (w), 3058 (w).

1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H, CHAr), 8.01 (dd, 3J = 8.6, 4J = 1.7 Hz, 1H, CHAr),

7.95 – 7.79 (m, 3H, CHAr), 7.64 – 7.41 (m, 7H, CHAr), 7.23 (d, 5J = 0.7 Hz, 1H, CHAr).


13C NMR (75 MHz, CDCl3) δ 152.1, 139.9 (CAr), 133.6 (2CAr), 132.2 (t, 2J = 27.9 Hz,

C-CF3), 129.8 (CHAr), 129.1 (2CHAr), 128.7, 128.4, 127.9 (CHAr), 126.9 (2CHAr), 126.6, 126.5,

125.0, 123.9 (CHAr), 107.6 – 107.3 (m, 1CHAr), signal of one CAr and CF2CF3 could not be

detected.

GC-MS (EI, 70 eV): m/z (%) = 388 (100), 269 (7), 194 (6), 127 (16), 77 (18).


3-([1,1'-Biphenyl]-4-yl)-5-(perfluoroethyl)-1-phenyl-1H-pyrazole 5.4n

APPENDIX

lvi


IR (ATR, cm-1): ν = 694 (s), 727 (s), 746 (s), 765 (s), 819 (s), 846

(m), 937 (s), 958 (s), 1020 (m), 1041 (s), 1072 (m), 1093 (s), 1134

(s), 1186 (s), 1219 (s), 1278 (w), 1331 (m), 1409 (w), 1441 (m), 1502 (m), 1597 (m), 3061 (w),

3132 (w).


7.51 – 7.21 (m, 8H, CHAr), 7.04 (s, 1H, CHAr).


13C NMR (63 MHz, CDCl3) δ 151.7, 141.6, 140.7, 139.9 (CAr), 132.1 (t, 2J = 27.4 Hz, C-CF3),

130.7 (CAr), 129.7 (CHAr), 129.1 (2CHAr), 129.0 (2CHAr), 127.7 (CHAr), 127.6 (2CHAr), 127.2

(2CHAr), 126.9 (2CHAr), 126.4 (2CHAr), 125.4 – 110.9 (m, CF2CF3), 107.4 – 107.1 (m, 1CHAr).

GC-MS (EI, 70 eV): m/z (%) = 414 (100), 395 (3), 345 (5), 295 (4), 207 (3), 152 (8), 116 (1),

77 (8).


5-(Perfluoropropyl)-1,3-diphenyl-1H-pyrazole 5.4o


IR (ATR, cm-1): ν = 532 (m), 590 (m), 648 (s), 692 (s), 746 (s), 765 (s),

777 (s), 814 (s), 874 (s), 957 (m), 1003 (m), 1026 (m), 1078 (m), 1109

(s), 1138 (s), 1182 (s), 1223 (s), 1344 (s), 1443 (m), 1500 (s), 1595 (w), 3053 (w), 3157 (w).


3H, CHAr), 7.12 (s, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -80.04 (t, 3JF-F = 10.1 Hz), -103.84 – -104.15 (m),

-124.86 – -125.05 (m).

13C NMR (63 MHz, CDCl3) δ 152.1, 139.9 (CAr), 132.3 (t, 2J = 28.7 Hz, C-CF3), 131.7 (CAr),

130.0 (CHAr), 129.3 (2CHAr), 129.2 (2CHAr), 129.1 (CHAr), 127.4 (2CHAr), 126.3 (2CHAr),

125.8 – 92.5 (CF2CF2CF3), 108.0 – 107.6 (m, 1CHAr).

GC-MS (EI, 70 eV): m/z (%) = 388 (100), 269 (39), 77 (18).


3-(4-Methoxyphenyl)-5-(perfluoropropyl)-1-phenyl-1H-pyrazole (4p):

APPENDIX

lvii

Pale solid, 76% (160 mg). M.p.: 97–98 °C.

IR (ATR, cm-1): ν = 644 (m), 692 (s), 744 (s), 773 (s), 800 (s),

872 (s), 904 (m), 958 (m), 1006 (s), 1030 (s), 1070 (m), 1078

(m), 1109 (s), 1138 (s), 1178 (s), 1184 (s), 1223 (s), 1251 (s), 1344 (m), 1435 (s), 1446 (s),

1502 (s), 1523 (m), 1552 (w), 1596 (w), 1614 (m), 2835 (w), 2939 (w), 2964 (w), 3001 (w),

3066 (w).


5H, CHAr), 7.03 (s, 1H, CHAr), 7.01 – 6.96 (m, 1H, CHAr), 6.96 – 6.92 (m, 1H, CHAr), 3.85 (s,

3H, OCH3).

19F NMR (282 MHz, CDCl3) δ -80.05 (t, 3JF-F = 10.1 Hz), -103.83 – -104.18

(m), -124.90 – -125.02 (m).

13C NMR (63 MHz, CDCl3) δ 160.2, 151.9, 139.9 (CAr), 132.9 – 131.6 (m, 1CAr), 129.6 (CHAr),

128.9 (2CHAr), 127.3 (2CHAr), 127.1 (2CHAr), 124.5 (CAr), 114.3 (2CHAr), 107.2 – 106.9 (m,

1CHHetAr), 55.5 (OCH3). (signals of CF2CF2CF3 could not be detected).

GC-MS (EI, 70 eV): m/z (%) = 418 (100), 375 (4), 299 (12), 77 (9).


Ethyl 3-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-1-carboxylate 5.4q


IR (ATR, cm-1): ν = 3519.0 (w), 3117.7 (w), 2966.8 (w), 2842.0

(w), 1766.3 (s), 1613.6 (m), 1587.0 (m), 1464.0 (m), 1441.8

(m), 1293.7 (s), 1143.8 (s), 1006.6 (m), 946.1 (m), 834.4 (s), 746.3 (m), 680.4 (m), 554.2 (m).


2H, CHAr), 4.57 (q, 3J = 7.1 Hz, 2H, OCH2CH3), 3.85 (s, 3H, OCH3), 1.49 (t, 3J = 7.1 Hz, 3H,

OCH2CH3).

19F NMR (282 MHz, CDCl3) δ -60.03.

13C NMR (75 MHz, CDCl3) δ 161.1 (C-OCH3), 153.5 (CAr), 148.3 (C=O), 135.8 (q,

2J = 41.3 Hz, C-CF3), 128.0 (2CHAr), 123.1 (CAr), 119.3 (q, 1J = 269.1 Hz, CF3), 114.4 (2CHAr),

110.8 (q, 3J = 3.2 Hz, CHHetAr), 65.5 (OCH2CH3), 55.5 (OCH3), 14.1 (OCH2CH3).

GC-MS (EI, 70 eV): m/z (%) = 314 (47), 270 (12), 255 (17), 242 (100), 227 (58), 213 (17), 199

(36), 170 (12), 151 (22), 120 (5), 101 (5), 75 (6), 63 (5).

APPENDIX

lviii

HRMS (+EI): calcd. for C14H13O3F3N2 ([M]+): 314.08728, found: 314.08732.

Ethyl 3-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-1-carboxylate (4r):


IR (ATR, cm-1): ν = 3505.3 (w), 3171.4 (w), 3076.4 (w), 2996.6 (w),

2918.6 (w), 1761.2 (s), 1620.7 (w), 1591.2 (w), 1446.9 (s), 1304.1

(m), 1229.2 (m), 1141.8 (s), 1026.1 (m), 1032.2 (m), 949.0 (m), 840.6 (m), 747.9 (m), 676.2

(m), 552.1 (w).

1H NMR (300 MHz, CDCl3) δ 8.10 (td, 3J = 7.7, 4J = 1.8 Hz, 1H, CHAr), 7.47 – 7.34 (m, 1H,

CHAr), 7.30 (d, 4J = 3.5 Hz, 1H, CHAr), 7.27 – 7.10 (m, 2H, CHAr), 4.59 (q, 3J = 7.1 Hz, 2H,

OCH2CH3), 1.50 (t, 3J = 7.1 Hz, 3H, OCH2CH3).

19F NMR (282 MHz, CDCl3) δ -60.00, -115.67.

13C NMR (63 MHz, CDCl3) δ 160.8 (d, 1J = 251.0 Hz, CF), 148.8 (CAr), 148.1 (C=O), 135.5

(q, 2J = 42.0 Hz C-CF3), 131.5 (d, 3J = 8.6 Hz, CHAr), 129.2 (d, 4J = 2.8 Hz, CHAr), 124.7 (d,

3J = 3.5 Hz, CHAr), 119.3 (q, 1J = 269.2 Hz, CF3), 118.5 (d, 2J = 11.5 Hz, CAr), 116.4 (d,

2J = 21.9 Hz, CHAr), 114.5 – 113.4 (m, CHAr), 65.7 (OCH2CH3), 14.1 (OCH2CH3).

2-Phenyl-3-(trifluoromethyl)-4,5,6,7,8,9,10,11,12,13-decahydro-2H-cyclododeca[c]pyrazo

le 5.4s


IR (ATR, cm-1): ν = 546 (m), 692 (s), 771 (s), 993 (s), 1086 (s), 1111 (s),

1168 (s), 1242 (m), 1309 (m), 1329 (m), 1350 (m), 1452 (m), 1504 (s),

1556 (w), 1595 (m), 2856 (m), 2904 (m), 2933 (m).

1H NMR (250 MHz, CDCl3) δ 7.44 (s, 5H, CHAr), 2.73 – 2.47 (m, 4H, CH2), 1.90 – 1.62 (m,

4H, CH2), 1.59 – 1.30 (m, 12H, CH2).

19F NMR (282 MHz, CDCl3) δ -55.61.

13C NMR (63 MHz, CDCl3) δ 153.2, 140.1 (CAr), 129.0 (2CHAr), 129.0 (q, 2J = 37.2 Hz,

C-CF3), 128.9 (CHAr), 126.2 (2CHAr), 122.9 (q, 3J = 3.2 Hz, CAr), 120.9 (q, 1J = 269.4 Hz, CF3),

28.9, 28.3, 26.0, 25.8, 25.4, 25.2 (CH2), 23.0 (2CH2), 22.9, 20.8(CH2).

GC-MS (EI, 70 eV): m/z (%) = 350 (100), 331 (9), 307 (50), 293 (41), 281 (71), 267 (36), 253

(43), 240 (79), 77 (40).


APPENDIX

lix

2-Phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-indazole 5.4t

Yellow oil, 82% (109 mg).

IR (ATR, cm-1): ν = 546 (m), 681 (m), 692 (s), 744 (m), 766 (s), 914 (m), 964

(m), 993 (s), 1028 (m), 1074 (s), 1097 (s), 1116 (s), 1149 (s), 1170 (s), 1213

(m), 1296 (m), 1352 (m), 1377 (m), 1464 (m), 1504 (s), 1574 (w), 1598 (m),

2854 (w), 2939 (m).

1H NMR (300 MHz, CDCl3) δ 7.49 – 7.37 (m, 5H, CHAr), 3.07 – 2.53 (m, 4H, CH2), 2.13 – 1.61

(m, 4H, CH2).

19F NMR (282 MHz, CDCl3) δ -55.92.

13C NMR (75 MHz, CDCl3) δ 150.2, 139.8 (CAr), 129.0 (2CHAr), 128.9 (CHAr), 128.1 (q,

2J = 38.2 Hz, C-CF3), 125.9 (2CHAr), 120.9 (q, 1J = 269.4 Hz, CF3), 119.8 (q, 3J = 1.7 Hz, CAr),

23.4, 22.8, 22.8 (CH2), 20.9 (q, 4J= 1.3 Hz, CH2).

GC-MS (EI, 70 eV): m/z (%) = 266 (100), 247 (6), 238 (48), 217 (4), 197 (52), 77(39).

HRMS (EI): calcd. For C14H13F3N2 ([M]+): 266.10253, found: 266.10212.

2-Phenyl-3-(trifluoromethyl)-4,5-dihydro-2H-indazole 5.4u

Brown oil, 66% (87 mg).

IR (ATR, cm-1): ν = 536 (m), 596 (m), 661 (m), 690 (s), 765 (s), 993 (s), 1095

(s), 1117 (s), 1163 (s), 1207 (m), 1304 (m), 1325 (m), 1377 (m), 1462 (m),

1502 (s), 1577 (w), 1597 (m), 1705 (w), 2837 (w), 2898 (w), 2937 (w), 3060

(w).

1H NMR (250 MHz, CDCl3) δ 7.53 – 7.32 (m, 5H, CHAr), 6.60 (dt, 3J = 9.9, 4J = 2.0 Hz, 1H,

CH=CH), 6.14 (dt, 3J = 9.9, 3J = 4.3 Hz, 1H, CH=CH), 3.08 – 2.78 (m, 2H, CH2), 2.55 – 2.36

(m, 2H, CH2).

19F NMR (282 MHz, CDCl3) δ -56.16.

13C NMR (63 MHz, CDCl3) δ 148.6, 139.7 (CAr), 131.5 (CH=CH), 129.1 (2CHAr), 128.9

(CHAr), 127.7 (q, 2J = 38.4 Hz, C-CF3), 125.9 (2C, CHAr), 120.8 (q, 1J = 269.6 Hz, CF3), 119.7

(CHAr). 118.7 (q, 3J = 1.8 Hz, CAr), 23.4 (CH2), 18.5 (q, 4J = 1.3 Hz, CH2).

GC-MS (EI, 70 eV): m/z (%) = 314 (100), 245 (33), 218 (10), 77 (27), 51 (12).


2-Phenyl-3-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole 5.4v

APPENDIX

lx

Brown solid, 82% (130 mg). M.p.: 78–79 °C.

IR (ATR, cm-1): ν = 549 (m), 648 (m), 696 (s), 731 (s), 781 (s), 897 (m),

945 (m), 987 (s), 1026 (m), 1047 (s), 1103 (s), 1157 (s), 1174 (s), 1226

(s), 1267 (m), 1307 (m), 1331 (m), 1352 (m), 1377 (m), 1446 (s), 1500

(s), 1595 (m), 2848 (w), 2901 (w), 2964 (w).


7.36 – 7.26 (m, 3H, CHAr), 3.16 – 2.77 (m, 4H, CH2).

19F NMR (282 MHz, CDCl3) δ -56.04.

13C NMR (75 MHz, CDCl3) δ 148.9, 139.8, 136.5 (CAr), 129.2 (CHAr), 129.2 (2CHAr), 128.6

(CAr), 128.5, 128.5 (CHAr), 128.3 (q, 2J = 38.3 Hz, C-CF3), 127.2 (CHAr), 126.2 (2CHAr), 122.8

(CHAr), 120.7 (q, 1J = 269.6 Hz, CF3), 120.1 (q, 3J = 1.8 Hz, CAr), 28.9 (CH2), 19.4 (q,

4J = 1.3 Hz, CH2).

GC-MS (EI, 70 eV): m/z (%) = 314 (100), 245 (33), 218 (10), 142 (13), 115 (10), 77 (27).

HRMS (EI): calcd. For C18H13F3N2 ([M]+): 314.10253, found: 314.10234.

5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole 5.5a

Compound 5.5a was synthesized following the general procedure using

4-methoxyacetophenone, ethyl carbamate for the first step and ethyl trifluoroacetate for the next

step. After adding ethyl trifluoroacetate, the reaction temperature was allowed to rise to 20 °C

and stirred for 30 min. Then the solvent was removed under reduced pressure. After that, the

residue was dissolved in toluene and 2 mmol (4 eq) of PTSA was added. The reaction mixture

was stirred under reflux for 8 h. After cooling, a saturated aqueous solution of NaHCO3 was

added until no evolution of CO2 was observed. Then THF was removed and the remained water

was extracted with ethyl acetate (10 mLx3). Combined organic layers were dried with MgSO4

and the solvent was removed under reduced pressure. The residue was purified by

chromatography (silica gel, heptane/DCM). The product was isolated as a white solid (51%, 62

mge).

M.p.: 147–148 °C.

IR (ATR, cm-1): ν = 3225.7 (w), 2974.4 (w), 2845.7 (w), 1614.5

(m), 1574.2 (m), 1516.7 (m), 1490.1 (m), 1458.8 (s), 1440.5 (m),

1274.9 (s), 1243.7 (s), 1109.9 (s), 1056.2 (s), 980.9 (m), 836.3 (s), 795.3 (s), 742.4 (m).

APPENDIX

lxi

1H NMR (300 MHz, CDCl3) δ 9.24 (s, br, 1H), 7.95 – 7.31 (m, 2H, CHAr), 7.11 – 6.77 (m, 2H,

CHAr), 6.66 – 6.62 (m, 1H, CHAr), 3.85 (s, 3H, OCH3).

19F NMR (282 MHz, CDCl3) δ -62.17 (s).

13C NMR (75 MHz, CDCl3) δ 160.7, 145.2(CAr), 143.7 (q, 2J = 38.1 Hz, C-CF3), 127.3 (2CHAr),

121.3 (q, 1J = 268.6 Hz, CF3), 120.7 (CAr), 114.8 (2CHAr), 100.5 (q, 3J = 1.8 Hz, CHHetAr), 55.5

(OCH3).

GC-MS (EI, 70 eV): m/z (%) = 242 (100), 227 (41), 223 (10), 199 (41), 169 (3), 151 (24).


5-(4-Methoxyphenyl)-3-(perfluoroethyl)-1H-pyrazole 5.5b

Compound 5.5b was synthesized following the procedure for

compound 5.5a using 4-methoxyacetophenone for the first step

and ethyl pentafluoropropionate for the next step. The product

was isolated as pale yellow solid (56%, 82 mg). M.p.: 137–138 °C.

IR (ATR, cm-1): ν = 3185.5 (w), 3142.1 (w), 3033.4 (w), 1619.0 (m), 1513.2 (s), 1330.6 (m),

1258.5 (s), 1185.6 (s), 1029.1 (s), 933.0 (s), 830.5 (m), 747.8 (m), 614.4 (m).

1H NMR (300 MHz, MeOD) δ 7.90 – 7.49 (m, 2H, CHAr), 7.16 – 6.94 (m, 2H, CHAr), 6.86 (s,

1H, CHAr), 3.86 (s, 3H, OCH3).

19F NMR (282 MHz, MeOD) δ -86.12, -114.10.

13C NMR (63 MHz, MeOD) δ 161.9 (C-OCH3), 128.3 (2CHAr), 115.6 (2CHAr), 102.2 (CHHetAr),

55.8 (OCH3), (signals of 3CAr and CF2CF3 could not be detected).

GC-MS (EI, 70 eV): m/z (%) = 292 (199), 277 (30), 249 (39), 223 (12), 151 (20), 111 (6).

HRMS (EI): calcd. for C12H9O1N2F5 ([M]+): 292.06296, found: 292.06263.

5-(4-Methoxyphenyl)-3-(perfluoropropyl)-1H-pyrazole 5.5c

Compound 5.5c was synthesized following the procedure for

compound 5.5a using 4-methoxyacetophenone for the first step

and ethyl heptafluorobutyrate for the next step. The product was

isolated as pale yellow solid (57%, 98 mg). M.p.: 127–128 °C.

IR (ATR, cm-1): ν = 3144.1 (w), 3031.2 (w), 2947.1 (w), 1890.6 (w), 1617.6 (m), 1512.5 (s),

1427.8 (m), 1348.6 (m), 1311.7 (m), 1255.9 (m), 1229.3 (s), 1178.2 (s), 1106.6 (s), 1029.6 (m),

1000.1 (m), 874.2 (s), 829.8 (m), 746.3 (s), 652.1 (m), 620.4 (m).

APPENDIX

lxii

1H NMR (300 MHz, MeOD) δ 7.78 – 7.47 (m, 2H, CHAr), 7.22 – 6.91 (m, 2H, CHAr), 6.85 (s,

1H, CHAr), 3.85 (s, 3H).

19F NMR (282 MHz, MeOD) δ -81.15 – -82.64 (m), -111.79 (d, 3J = 9.5 Hz),

-127.00 – -130.06 (m).

13C NMR (63 MHz, MeOD) δ 161.9 (C-OCH3), 146.4, 143.0 (CAr), 128.3 (2CHAr), 122.2 (CAr),

115.6 (2CHAr), 102.4 (CHHetAr), 55.8 (OCH3) (signals of CF2CF2CF3 could not be detected).

GC-MS (EI, 70 eV): m/z (%) = 342 (100), 327 (18), 299 (25), 223 (29), 208 (4), 180 (5), 151

(15), 111 (6). HRMS (EI): calcd. for C13H9O1N2F7 ([M]+): 342.05976, found: 342.05959.

5-(Naphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole 5.5d

Compound 5.5d was synthesized following the procedure for

compound 5.5a using 2-acetonaphthone for the first step and ethyl

trifluoroacetate for the next step. The product was isolated as white

solid (78%,102 mg). M.p.: 180–181 °C.

IR (ATR, cm-1): ν = 3227.5 (w), 3043.6 (w), 2923.5 (w), 1631.9 (w), 1608.5 (w), 1582.5 (w),

1567.3 (w), 1500.0 (m), 1474.0 (w), 1255.6 (m), 1150.1 (s), 1120.6 (s), 1103.6 (s), 992.0 (m),

860.5 (m), 803.6 (s), 741.1 (s), 713.1 (m), 679.4 (m), 601.7 (m).

1H NMR (300 MHz, MeOD) δ 8.26 (s, 1H, CHAr), 8.11 – 7.72 (m, 4H, CHAr), 7.56 (dd,

3J = 6.3 Hz, 4J = 3.0 Hz, 2H, CHAr), 7.10 (s, 1H, CHAr).

19F NMR (282 MHz, MeOD) δ -63.58.

13C NMR (75 MHz, Acetone) δ 145.5 (CAr), 144.3 (q, 2J = 37.5 Hz, C-CF3), 134.4, 134.4 (CAr),

129.9, 129.1, 128.7, 127.8, 127.7 (CHAr), 126.7 (CAr), 125.6, 124.3 (CHAr), 122.9 (q,

1J = 267.5 Hz, CF3), 102.1 (CHAr).

GC-MS (EI, 70 eV): m/z (%) = 262 (100), 243 (7), 214 (10), 183 (6), 165 (22), 152 (1), 139 (4),

127 (7), 69 (3).

HRMS (+ESI): calcd. for C14H10F3N2 ([M+H]+): 263.07906, found: 263.07925.

5-(Naphthalen-2-yl)-3-(perfluoroethyl)-1H-pyrazole 5.5e

Compound 5.5e was synthesized following the procedure for


pentafluoropropionate for the next step. The product was isolated

as pale yellow solid (86%, 134 mg). M.p.: 124–126 °C.

APPENDIX

lxiii

IR (ATR, cm-1): ν = 3147.0 (w), 3114.4 (w), 2933.1 (w), 1955.6 (w), 1906.3 (w), 1785.8 (w),

1679.0 (w), 1583.7 (w), 1566.5 (w), 1513.6 (w), 1431.1 (w), 1332.5 (s), 1214.1 (s), 1183.3 (s),

1131.7 (s), 1069.4 (m), 1028.9 (s), 940.5 (s), 801.5 (m), 745.4 (s), 619.4 (m).

1H NMR (300 MHz, MeOD) δ 8.21 (d, 4J = 4.6 Hz, 1H, CHAr), 8.08 – 7.70 (m, 4H, CHAr),

7.62 – 7.42 (m, 2H, CHAr), 7.07 (s, 1H, CHAr).

19F NMR (282 MHz, MeOD) δ -86.02, -114.00.

13C NMR (63 MHz, MeOD) δ 146.4, 134.8 (CAr), 130.1, 129.3, 128.8 (CHAr), 127.9 (2CHAr),

126.9 (CAr), 125.8, 124.4, 103.3 (CHAr), (signals of 2CAr and CF2CF3 could not be detected).

GC-MS (EI, 70 eV): m/z (%) = 312 (100), 293 (5), 243 (18), 214 (13), 194 (4), 165 (17), 121

(11), 82 (3), 69 (2).


3-(Perfluoropropyl)-5-(naphthalen-2-yl)-1H-pyrazole 5.5f

Compound 5.5f was synthesized following the procedure for


heptafluorobutyrate for the next step. The product was isolated as

pale yellow solid (64%, 116 mg). M.p.: 181–182 °C.

IR (ATR, cm-1): ν = 3183.6 (w), 3067.3 (w), 2877.8 (w), 1565.2 (w), 1512.8 (w), 1415.8 (w),

1349.1 (m), 1224.1 (m), 1176.5 (s), 1103.7 (m), 1000.7 (m), 874.8 (m), 791.3 (m), 744.3 (m),

651.2 (m).

1H NMR (300 MHz, MeOD) δ 8.26 (s, 1H, CHAr), 8.12 – 7.72 (m, 4H, CHAr), 7.68 – 7.44 (m,

2H, CHAr), 7.11 (s, 1H, CHAr).

19F NMR (282 MHz, MeOD) δ -81.78 (t, 3JF-F = 9.5 Hz), -111.71 (d, 3JF-F = 8.6 Hz), -128.28

(s).

13C NMR (75 MHz, Acetone) δ 145.7, 134.4, 134.4 (CAr), 129.9, 129.2, 128.7, 127.8, 127.8,

125.7, 124.3, 103.6 (CHAr), (signals of 2CAr and CF2CF2CF3 could not be detected).

GC-MS (EI, 70 eV): m/z (%) = 362 (100), 343 (9), 243 (34), 214 (17), 194 (4), 165 (14), 122

(13), 83 (4), 69 (4).


3-(Trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole 5.5g

APPENDIX

lxiv

Compound 5.5g was synthesized following the procedure for

compound 5.5a using 4-trifluoromethylacetophenone for the first

step and ethyl trifluoroacetate for the next step. The product was

isolated as white solid (75%, 105 mg). M.p.: 135–136 °C.

IR (ATR, cm-1): ν = 3239.9 (w), 3161.7 (w), 3066.3 (w), 2987.4 (w), 1914.8 (w), 1790.5 (w),

1738.4 (w), 1671.9 (w), 1622.3 (w), 1587.6 (w), 1494.7 (w), 1325.4 (m), 1253.0 (m), 1172.6

(m), 1109.0 (s), 1068.0 (m), 982.9 (m), 916.7 (m), 813.6 (m), 747.3 (m), 661.5 (m), 592.3 (m).

1H NMR (300 MHz, MeOD) δ 7.95 (d, 3J = 8.2 Hz, 2H, CHAr), 7.80 (d, 3J = 8.3 Hz, 2H, CHAr),

7.12 (s, 1H, CHAr).

19F NMR (282 MHz, MeOD) δ -63.66, -64.34.

13C NMR (75 MHz, CDCl3) δ 144.2 (CAr), 143.5 (q, 2J = 38.0 Hz, CAr), 131.5 (q, 2J = 33.0 Hz,

C-CF3), 131.2 (CAr), 126.4 (q, 4J = 3.8 Hz, 2CHAr), 125.8 (2CHAr), 123.7 (q, 1J = 272.3 Hz,

CF3), 120.7 (q, 1J = 269.0 Hz, CF3), 102.1 (CHHetAr).

GC-MS (EI, 70 eV): m/z (%) = 280 (100), 261 (23), 231 (7), 211 (20), 201 (5), 182 (15), 164

(4), 145 (8), 133 (49, 87 (2), 69 (6).


5-(Perfluoroethyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole 5.5h

Compound 5.5h was synthesized following the procedure for


step and ethyl pentafluoropropionatefor the next step. The product

was isolated as white solid (74%, 122 mg). M.p.: 142–143 °C.

IR (ATR, cm-1): ν = 3191.2 (w), 3032.7 (w), 2887.0 (w), 1623.7 (w), 1590.6 (w), 1465.6 (w),

1429.3 (w), 1325.2 (s), 1225.8 (s), 1194.1 (s), 1125.4 (s), 1063.8 (m), 1030.5 (m), 973,8 (m),

939.2 (m), 841.6 (m), 807.8 (m), 750.1 (m), 693.5 (m), 622.0 (w), 591.5 (w).


7.14 (s, 1H, CHAr).

19F NMR (282 MHz, MeOD) δ -64.34, -86.12, -114.07.

13C NMR (75 MHz, CDCl3) δ 144.6 (CAr), 131.7 (q, 2J = 32.9 Hz, C-CF3), 129.2 (CAr), 126.4

(q, 4J = 3.8 Hz, 2CHAr), 125.9 (2CHAr), 123.8 (q, 1J = 272.2 Hz, CF3), 103.9 (CHHetAr), (signals

of 1CAr and CF2CF3 could not be detected).

APPENDIX

lxv

GC-MS (EI, 70 eV): m/z (%) = 330 (81), 311 (21), 261 (100), 232 (4), 213 (9), 182 (6), 164

(18), 145 (5), 121 (5), 105 (5), 69 (6).


5-(Perfluoropropyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole 5.5i

Compound 5.5i was synthesized following the procedure for


step and ethyl heptafluorobutyrate for the next step. The product

was isolated as white solid (67%, 127 mg). M.p. 109–110 °C.

IR (ATR, cm-1): ν = 3171.2 (w), 3034.4 (w), 2950.7 (w), 2887.4 (w), 1623.5 (w), 1591.8 (w),

1467.1 (w), 1424.8 (w), 1326.4 (s), 1276.0 (w), 1232.3 (s), 1171.5 (m), 1109.2 (s), 1063.0 (s),

1001.4 (m), 876.1 (m), 842.4 (m), 810.1 (m), 747.9 (m), 652.6 (m), 592.2 (m).


7.14 (s, 1H, CHAr).

19F NMR (282 MHz, MeOD) δ -64.35 (s), -81.84 (t, 3J = 9.6 Hz), -111.76 (s), -128.29 – -128.38

(m).

(Due to there are many Fs in the molecule, the signals of carbons are splited and very difficult

to identify.)

GC-MS (EI, 70 eV): m/z (%) = 380 (64), 361 (23), 261 (100), 213 (8), 182 (5), 164 (17), 69 (6).


Synthesis of 2-phenyl-3-(trifluoromethyl)-2H-indazole 5.6a

To a solution of 5.4s (100 mg) in toluene (7 mL), DDQ (2 equiv.) was added. The reaction

mixture was stirred under reflux for 3h. Then the reaction mixture was cooled to room

temperature and ethyl acetate (10 mL) and water (10 mL) were added. The organic layer was

separated and washed with water three times. After drying and removal of solvent, the residue

was purified by chromatography (silica gel, n-heptane/DCM). The product was isolated as a

yellow oil (71%, 71 mg).

IR (ATR, cm-1): ν = 534 (m), 567 (m), 627 (m), 640 (m), 692 (s), 743 (s), 768

(s), 829 (m), 914 (m), 933 (m), 989 (s), 1001 (s), 1030 (m), 1074 (s), 1103 (s),

1147 (s), 1174 (s), 1223 (s), 1298 (s), 1381 (w), 1429 (s), 1469 (m), 1500 (s),

1522 (m), 1551 (w), 1597 (m), 2361 (w), 2858 (w), 2929 (w), 3066 (w).

APPENDIX

lxvi


7.49 – 7.37 (m, 1H, CHAr), 7.37 – 7.27 (m, 1H, CHAr).

19F NMR (282 MHz, CDCl3) δ -54.47.

13C NMR (75 MHz, CDCl3) δ 148.3, 139.7 (CAr), 130.1 (CHAr), 129.2 (2CHAr), 127.4 (CHAr),

126.3 (2CHAr), 125.2 (CHAr), 123.8 (q, 2J = 39.5 Hz, C-CF3), 121.7 (CAr), 121.1 (q,

1J = 269.0 Hz, CF3), 119.5 (q, 4J = 1.7 Hz, CHAr), 118.6 (CHAr).

GC-MS (EI, 70 eV): m/z (%) = 262 (100), 236 (7), 193 (34), 166 (11), 77 (15), 51 (12).


Synthesis of 2-phenyl-3-(trifluoromethyl)-2H-benzo[g]indazole 5.6b

To a solution of 5.4t (100 mg) in toluene (7 mL), DDQ (2 equiv.) was added. The reaction

mixture was stirred under reflux for 3h. Then the reaction mixture was cooled to room

temperature and ethyl acetate (10 mL) and water (10 mL) were added. The organic layer was

separated and washed with water three times. After drying and removal of solvent, the residue

was purified by chromatography (silica gel, n-heptane/DCM). The product was isolated as a

pale yellow solid (90%, 90 mg). M.p.: 100–102 °C.

IR (ATR, cm-1): ν = 549 (s), 681 (s), 746 (s), 767 (s), 804 (s), 885 (m),

982 (s), 1045 (s), 1099 (s), 1176 (s), 1217 (s), 1238 (m), 1269 (m), 1309

(m), 1385 (w), 1441 (s), 1473 (m), 1504 (s), 1558 (w), 1597 (m), 3024

(w), 3049 (w).

1H NMR (300 MHz, CDCl3) δ 8.66 (dd, 3J = 5.7, 4J = 3.5 Hz, 1H), 7.93 – 7.80 (m, 1H),

7.76 – 7.52 (m, 9H).

19F NMR (282 MHz, CDCl3) δ -54.74 (s).

13C NMR (63 MHz, CDCl3) δ 146.1, 139.7, 132.3 (CAr), 129.8 (CHAr), 129.1 (2CHAr), 128.5,

127.7, 127.5, 127.3, 126.4, 126.3 (CHAr), 125.0 (CAr), 124.7 (q, 2J = 39.8 Hz, C-CF3), 122.5

(CHAr), 120.9 (q, 1J = 269.2 Hz, CF3), 119.3 (CAr), 116.9 (q, 4J = 1.9 Hz, CHAr).

GC-MS (EI, 70 eV): m/z (%) = 312 (100), 242 (30), 77 (10).

HRMS (EI): calcd. for C18H11F3N2([M]+): 312.08688, found: 312.08667.

3-(4-methoxyphenyl)-5-(trifluoromethyl)isoxazole 5.8a

APPENDIX

lxvii

Compound 5.8a was synthesized following the general procedure using

4-methoxyacetophenone, hydroxylamine for the first step and ethyl trifluoroacetate for the next

step. The product was isolated as a white solid (57%, 69 mg). M.p.

76-78 °C.

IR (ATR, cm-1): ν = 3114.5 (w), 2963.7 (w), 2844.2 (w), 1611.5

(m), 1532.2 (w), 1459.8 (m), 1432.7 (m), 1319.7 (m), 1242.4 (m),

1174.7 (m), 1114.0 (s), 1023.3 (m), 966.8 (m), 915.7 (m), 837.2 (m), 821.7 (m), 747.2 (m),

680.0 (w).

1H NMR (300 MHz, CDCl3) δ 7.82 – 7.68 (m, 2H, CHAr), 7.04 – 6.96 (m, 2H, CHAr), 6.94 (d,

5J = 0.9 Hz, 1H, CHAr), 3.87 (s, 3H, OCH3).

19F NMR (282 MHz, CDCl3) δ -64.24.

13C NMR (75 MHz, CDCl3) δ 162.3, 161.8 (CAr), 159.1 (q, 2J = 42.4 Hz, C-CF3), 128.6

(2CHAr), 119.9 (CAr), 118.1 (q, 1J = 270.3 Hz, CF3), 114.7 (2CHAr), 103.3 (d, 3J = 2.1 Hz,

CHHetAr), 55.5 (OCH3).

GC-MS (EI, 70 eV): m/z (%) = 243 (82), 174 (82), 146 (100), 131 (14), 119 (7), 103 (9), 92

(11), 76 (18), 63 (15), 50 (9).


3-(naphthalen-2-yl)-5-(trifluoromethyl)isoxazole 5.8b

Compound 5.8b was synthesized following the general procedure using 2-acetonaphthone,

hydroxylamine for the first step and ethyl trifluoroacetate for the next step. The product was

isolated as a white (62%, 82 mg). M.p. 103–104 °C.

IR (ATR, cm-1): ν = 3232.3 (w), 3126.3 (w), 2921.0 (w), 1631.3 (w),

1486.7 (m), 1438.6 (m), 1303.8 (m), 1143.6 (s), 1104.9 (s), 1057.6

(m), 964.1 (m), 901.5 (m), 827.7 (s), 745.5 (m), 633.1 (w).



19F NMR (282 MHz, CDCl3) δ -64.15.

13C NMR (75 MHz, CDCl3) δ 162.8 (CAr), 159.4 (q, 2J = 42.7 Hz, C-CF3), 134.5, 133.2 (CAr),

129.3, 128.7, 128.1, 127.7, 127.3, 127.2 (CHAr), 124.8 (CAr), 123.7 (CHAr), 118.1 (d,

1J = 270.5 Hz, CF3), 103.7 (d, 3J = 2.1 Hz, CHHetAr).

APPENDIX

lxviii

GC-MS (EI, 70 eV): m/z (%) = 263 (100), 194 (72), 166 (41), 139 (21), 127 (68), 115 (12), 97

(8), 69 (10).

HRMS (+ESI): calcd. for C14H9O1F3N1 ([M+H]+): 264.06307, found: 264.06321.

APPENDIX

lxix

Crystal data and structure refinement

Crystal data and structure refinement for compound 2.6h

is_cm11

Crystal data

Chemical formula C24H16FNO2

Mr 369.38

Crystal system, space group Monoclinic, P21/c

Temperature (K) 173

a, b, c (Å) 7.7148 (5), 20.3158 (13), 11.7110 (8)

β (°) 91.418 (4)

V (Å3) 1834.9 (2)

Z 4

Radiation type Mo Kα

µ (mm−1) 0.09

Crystal size (mm) 0.46 × 0.12 × 0.10

Data collection

Diffractometer Bruker Apex Kappa II-CCD-

diffractometer

Absorption correction Multi-scan

(SADABS; Sheldrick, 2004)

Tmin, Tmax 0.959, 0.991

No. of measured, independent and

observed [I > 2σ(I)] reflections

25493, 4882, 2572

Rint 0.071

(sin θ/λ)max (Å−1) 0.682

Refinement

R[F2 > 2σ(F2)], wR(F2), S 0.049, 0.126, 1.00

No. of reflections 4882

No. of parameters 253

H-atom treatment H-atom parameters constrained

Δρmax, Δρmin (e Å−3) 0.20, −0.21

APPENDIX

lxx

Crystal data and structure refinement for compound 3.3i

is_indolo_d2

Crystal data

Chemical formula C21H14FN

Mr 299.33

Crystal system, space group Monoclinic, P21/c

Temperature (K) 173

a, b, c (Å) 10.5670 (7), 20.0282 (12), 6.8420 (5)

β (°) 95.652 (2)

V (Å3) 1440.99 (17)

Z 4


µ (mm−1) 0.09

Crystal size (mm) 0.33 × 0.27 × 0.22

Data collection

Diffractometer Bruker Apex Kappa II-CCD-

diffractometer



Tmin, Tmax 0.671, 0.746



19527, 3832, 2993

Rint 0.038

(sin θ/λ)max (Å−1) 0.682

Refinement

R[F2 > 2σ(F2)], wR(F2), S 0.052, 0.129, 1.10



No. of restraints 68


APPENDIX

lxxi

Δρmax, Δρmin (e Å−3) 0.21, −0.20

Crystal data and structure refinement for compound 3.7j

is_es4

Crystal data

Chemical formula C20H14N2O

Mr 298.33

Crystal system, space group Triclinic, P

Temperature (K) 173

a, b, c (Å) 12.2153 (2), 13.5599 (2), 18.6521 (3)

α, β, γ (°) 95.666 (1), 104.369 (1), 107.679 (1)

V (Å3) 2800.32 (8)

Z 8


µ (mm−1) 0.09

Crystal size (mm) 0.55 × 0.28 × 0.19

Data collection

Diffractometer Bruker-Nonius Apex X8-CCD-

diffractometer



Tmin, Tmax 0.707, 0.746



93666, 18586, 13060

Rint 0.033

(sin θ/λ)max (Å−1) 0.735

Refinement

R[F2 > 2σ(F2)], wR(F2), S 0.050, 0.147, 1.01




APPENDIX

lxxii

Δρmax, Δρmin (e Å−3) 0.47, −0.28

Crystal data and structure refinement for compound 4.3a

is_tn_hb

Crystal data

Chemical formula C22H14S

Mr 310.39


Temperature (K) 123

a, b, c (Å) 6.0433 (2), 10.7998 (3), 12.1236 (3)

α, β, γ (°) 108.612 (1), 92.292 (1), 95.272 (1)

V (Å3) 744.69 (4)

Z 2


µ (mm−1) 0.21

Crystal size (mm) 0.29 × 0.20 × 0.14

Data collection


diffractometer



Tmin, Tmax 0.722, 0.746



16019, 4325, 3897

Rint 0.021

(sin θ/λ)max (Å−1) 0.703

Refinement

R[F2 > 2σ(F2)], wR(F2), S 0.035, 0.096, 1.06




APPENDIX

lxxiii

Δρmax, Δρmin (e Å−3) 0.45, −0.26

Crystal data and structure refinement for compound 4.3b

is_thang1203

Crystal data

Chemical formula C23H16S

Mr 324.42


Temperature (K) 123

a, b, c (Å) 5.9864 (2), 11.0375 (4), 13.4379 (5)

α, β, γ (°) 112.071 (2), 96.127 (2), 92.844 (2)

V (Å3) 814.25 (5)

Z 2


µ (mm−1) 0.20

Crystal size (mm) 0.19 × 0.15 × 0.10

Data collection


diffractometer



Tmin, Tmax 0.710, 0.746



27542, 5885, 4610

Rint 0.029

(sin θ/λ)max (Å−1) 0.756

Refinement

R[F2 > 2σ(F2)], wR(F2), S 0.041, 0.112, 1.02




APPENDIX

lxxiv

Δρmax, Δρmin (e Å−3) 0.46, −0.26

APPENDIX

lxxv

List of tables

Table 2.1: Optimization for the synthesis of 2.4a ................................................................... 25

Table 2.2: Synthesis of 2.4 ...................................................................................................... 26

Table 2.3: Optimization of 2.6a ............................................................................................... 27

Table 2.4: Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones ................................................... 28

Table 2.5: Anticholinesterase activities of chromeno[3,4-b]pyrrol-4(3H)-ones ..................... 32

Table 2.6: Monoamine oxidase (A & B) activities of chromeno[3,4-b]pyrrol-4(3H)-ones .... 33

Table 3.1: Optimization for the synthesis of 3.3a ................................................................... 40

Table 3.2: Synthesis of alkynes 3.1 ......................................................................................... 41

Table 3.3: Synthesis of indolo[1,2-f]phenathridines ............................................................... 42

Table 3.4: Reaction of 1,2-bis(2-bromophenyl)ethyne 3.1f with amines ................................ 46

Table 3.5: Synthesis of 3-bromo-2-(alkynyl)pyridines ........................................................... 51

Table 3.6: Synthesis of 4-azaindolo[1,2-f]phenanthridines ..................................................... 52



Table 3.9: Absorption and emission spectroscopic data of azaindolo[1,2-f]phenanthridines . 60

Table 4.1: Synthesis of benzo[b]naphtho[2,1-d]thiophenes .................................................... 71

Table 4.2: Synthesis of naphtho[1,2-b]benzofurans ................................................................ 74

Table 4.3: Synthesis of benzo[a]carbazoles ............................................................................ 75

Table 5.1: Synthesis of pyrazoles 5.4 and 5.5 ......................................................................... 82

Table 5.2: Alkaline phosphatase AP (h-TNAP & h-IAP) and NPP (h-NPP1 & h-NPP3)

inhibition in presence of the synthesized compounds .............................................................. 88

APPENDIX

lxxvi

List of figures

Figure 1.1: Heterocycles in hydrogen-bonding interaction and complex with metal cation..... 2

Figure 1.2: Aromatic heterocycles as drugs .............................................................................. 3

Figure 1.3: Aromatic heterocycles applied in organic materials ............................................... 4

Figure 1.4: A general Pd(0)-catalytic cycle ............................................................................... 5

Figure 1.5: Selectivity of oxidative addition on substrates with many reactive centers ........... 7

Figure 1.6: Cross-coupling reaction involving transmetalation .............................................. 10

Figure 1.7: Phosphine ligands ................................................................................................. 17

Figure 1.8: Diphosphine ligands ............................................................................................. 18

Figure 2.1: Ningalin B and Lamellarin D derivatives ............................................................. 22

Figure 2.2: X-ray structure of 2.6h .......................................................................................... 31

Figure 2.3: Putative binding mode of 2.6i inside AChE receptor (PDB ID 3I6Z). ................. 34

Figure 2.4: Putative binding mode of 2.6i inside AChE receptor (PDB ID 3I6Z). ................. 34

Figure 2.5: Putative binding mode of 2.6p inside BuChE receptor (PDB ID 1P0I) ............... 35

Figure 2.6: Putative binding mode of 2.6p inside BuChE receptor (PDB ID 1P0I) ............... 35

Figure 3.1: Biologically active phenanthridines ...................................................................... 37

Figure 3.2: Phenanthridine derivatives with potential physical properties ............................. 38

Figure 3.3: X-ray crystal structure analysis of 3.3i ................................................................. 44

Figure 3.4: Azaindolo[1,2-f]phenanthridines applicable in electroluminescent devices ........ 48

Figure 3.5: X-ray crystallographic analysis of 3.7j. ................................................................ 54

Figure 3.6: Normalized absorption and corrected emission spectra of

azaindolo[1,2-f]phenanthridines in CH2Cl2. ............................................................................. 59

Figure 3.7: Arnoamine C & D ................................................................................................. 61

Figure 4.1: The structure of 4.3a determined by X-ray crystallographic analysis .................. 73

Figure 4.2: The structure of 4.3b determined by X-ray crystallographic analysis .................. 74

Figure 5.1: Drugs and agrochemicals containing trifluoromethylated pyrazoles.................... 78

Figure 5.2: Bioactive trifluoromethylated indazoles D and E ................................................. 85

APPENDIX

lxxvii

List of schemes

Scheme 1.1: Oxidative addition and reductive elimination ....................................................... 5

Scheme 1.2: Mechanisms of oxidative addition ........................................................................ 6

Scheme 1.3: Buchwald-Hartwig reaction .................................................................................. 8

Scheme 1.4: Mechanisms of ligand exchange ........................................................................... 9

Scheme 1.5: Transmetalation ..................................................................................................... 9

Scheme 1.6: Roles of base in Suzuki-Miyaura reaction .......................................................... 10

Scheme 1.7: Mechanism of Sonogashira reaction ................................................................... 11

Scheme 1.8: Migratory insertions ............................................................................................ 11

Scheme 1.9: Migratory insertion of CO ................................................................................... 12

Scheme 1.10: Migratory insertion of carbene .......................................................................... 12

Scheme 1.11: Cross-coupling reaction of N-tosylhydrazones involving carbene ................... 12

Scheme 1.12: Heck-Mizoroki reaction .................................................................................... 13

Scheme 1.13: Cationic mechanism of 1,2-migratory insertion ............................................... 13

Scheme 1.14: Neutral mechanism of 1,2-migratory insertion ................................................. 13

Scheme 1.15: Anionic mechanism of 1,2-migratory insertion ................................................ 14

Scheme 1.16: β-hydride elimination ........................................................................................ 14

Scheme 1.17: C-H arylation vs traditional cross-coupling reactions ....................................... 15

Scheme 1.18: Mechanisms C-H arylation ............................................................................... 15

Scheme 1.19: Intramolecular direct arylation .......................................................................... 16

Scheme 1.20: Approaches to the synthesis of indoles by Pd(0)-catalyzed domino reactions: 19

Scheme 1.21: Synthesis of indolo[2,3-a]carbazoles by Cacchi ............................................... 20

Scheme 1.22: Synthesis of indoles by one-pot three-component reaction by Ackemann ....... 20

Scheme 1.23: Approaches to the synthesis of carbazoles ........................................................ 20

Scheme 2.1: Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones ................................................ 23

Scheme 2.2: Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones by hydroamination ................ 24

Scheme 2.3: Synthesis of 3-bromo-4-(trifluoromethanesulfonyloxy)coumarin ...................... 24

Scheme 3.1: Domino reactions for the synthesis of fused-phenanthridines ............................ 39

Scheme 3.2: Reaction of 1-chloro-2-(phenylethynyl)benzene with 2-bromoaniline............... 44

Scheme 3.3: Proposed pathway for the reaction ...................................................................... 45

Scheme 3.4: Reaction of 1-bromo-2-((2-chlorophenyl)ethynyl)benzene with p-toluidine ..... 48

Scheme 3.5: Synthesis of azaindolo[1,2-f]phenanthridines via in situ benzyme ..................... 49

Scheme 3.6: Synthesis of azaindolo[1,2-f]phenanthridines ..................................................... 49

Scheme 3.7: Proposed pathway for the reaction ...................................................................... 50

Scheme 3.8: Synthesis of 3.6g ................................................................................................. 57

Scheme 3.9: Two-fold domino reaction .................................................................................. 58

Scheme 3.10: Retrosynthesis analysis of Arnoamines ............................................................ 61

Scheme 3.11: Proposed Synthesis of starting marterial ........................................................... 62

Scheme 3.12: Alternative starting material 3.13 ...................................................................... 62

Scheme 3.13: Domino reaction of 3.13 ................................................................................... 63

Scheme 4.1: Pathways of 6-endo-trig and 5-exo-trig cyclizations .......................................... 64

Scheme 4.2: Pd-catalyzed cyclization of dibrominated compounds with hydrazones ............ 65

Scheme 4.3: Tandem reaction of 3-bromo-2-(2’-chlorophenyl)benzo[b]thiophene 4.1a with

N-tosylhydrazone of acetophenone 4.2a .................................................................................. 66

APPENDIX

lxxviii

Scheme 4.4: Proposed mechanism of Pd-catalyzed cyclization of dibrominated compounds

with hydrazones. ....................................................................................................................... 68

Scheme 4.5: Tandem reaction of 2,2′-dibromobiphenyl 4.1b and

3-bromo-2-(2-bromophenyl)pyridine 4.1c. .............................................................................. 69

Scheme 4.6: Tandem reaction of 3-bromo-2-(2-bromophenyl)benzo[b]thiophene 4.1d and

N-tosylhydrazones. ................................................................................................................... 70

Scheme 5.1: One-pot cyclocondensation of 1,3-dicarbonyl dianions with α-azidoketones .... 77

Scheme 5.2: Synthesis of pyrazoles ......................................................................................... 79

Scheme 5.3: Synthesis of pyrazoles by cyclization of hydrazone 1,4-dianions ...................... 80

Scheme 5.4: Synthesis of pyrazoles 5.4 and 5.5 ...................................................................... 81

Scheme 5.5: Synthesis of 5.4s-v .............................................................................................. 85

Scheme 5.6: Synthesis of 5.6a and 5.6b .................................................................................. 86

Scheme 5.7: Synthesis of isoxazoles 5.8a, b ........................................................................... 86

APPENDIX

lxxix

List of References

[1] A. F. Pozharskiĭ, A. R. Katritzky, A. T. Soldatenkov, Heterocycles in life and society,

Wiley, Chichester West Sussex, 2011.

[2] J. A. Joule, K. Mills, Heterocyclic chemistry, Wiley, Oxford, 2010.

[3] V. Cechinel-Filho, Plant bioactives and drug discovery, Wiley, Hoboken, N.J., 2012.

[4] a) K. Brune, Acute Pain 1997, 1, 33–40; b) E. Ravina, The evolution of drug discovery,

Wiley-VCH, Weinheim, 2011.

[5] a) W. Jiang, Y. Li, Z. Wang, Chem. Soc. Rev. 2013, 42, 6113–6127; b) W. Wu, Y. Liu, D.

Zhu, Chem. Soc. Rev. 2010, 39, 1489–1502; c) Y. Lin, Y. Li, X. Zhan, Chem. Soc. Rev.

2012, 41, 4245–4272.

[6] K. E. Maly, Cryst. Growth Des. 2011, 11, 5628–5633.

[7] a) G. Horowitz, Adv. Mater. 1998, 10, 365–377; b) J. E. Anthony, J. S. Brooks, D. L. Eaton,

S. R. Parkin, J. Am. Chem. Soc. 2001, 123, 9482–9483.

[8] a) X. Wang, K.-C. Lau, J. Phys. Chem. C 2012, 116, 22749–22758; b) S.-Z. Weng, P.

Shukla, M.-Y. Kuo, Y.-C. Chang, H.-S. Sheu, I. Chao, Y.-T. Tao, ACS Catal. 2009, 1,

2071–2079; c) U. H. F. Bunz, Acc. Chem. Res. 2015, 48, 1676–1686.

[9] a) M. Cölle, J. Gmeiner, W. Milius, H. Hillebrecht, W. Brütting, Adv. Funct. Mater. 2003,

13, 108–112; b) R. Katakura, Y. Koide, Inorg. Chem. 2006, 45, 5730–5732; c) V. A.

Montes, R. Pohl, J. Shinar, P. Anzenbacher, JR, Chem. Eur. J. 2006, 12, 4523–4535.

[10] H. Yersin, Highly efficient OLEDs with phosphorescent materials, Wiley-VCH,

Weinheim, 2007.

[11] A. d. Meijere, S. Bräse, M. Oestreich, Metal-catalyzed cross-coupling reactions and

more, Wiley-VCH, Weinheim, 2014.

[12] J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry, Elsevier Science, 2006.

[13] J. Tsuji, Palladium reagents and catalysts, John Wiley & Sons, Chichester, West

Sussex, Hoboken, N.J., 2004.

[14] C. Torborg, M. Beller, Adv. Synth. Catal. 2009, 351, 3027–3043.

[15] a) P. G. Gildner, T. J. Colacot, Organometallics 2015, 34, 5497–5508; b) X.-F. Wu, P.

Anbarasan, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2010, 49, 9047–9050.

[16] E.-i. Negishi, Handbook of organopalladium chemistry for organic synthesis, John

Wiley & Sons, Inc, New York, Great Britain, 2002.

[17] a) B. U. W. Maes, S. Verbeeck, T. Verhelst, A. Ekomie, N. von Wolff, G. Lefevre, E.

A. Mitchell, A. Jutand, Chem. Eur. J. 2015, 21, 7858–7865; b) C. Amatore, F. Pfluger,

Organometallics 1990, 9, 2276–2282; c) M. Portnoy, D. Milstein, Organometallics 1993,

12, 1665–1673.

[18] T. N. Ngo, F. Janert, P. Ehlers, D. H. Hoang, T. T. Dang, A. Villinger, S. Lochbrunner,

P. Langer, Org. Biomol. Chem. 2016, 14, 1293–1301.

APPENDIX

lxxx

[19] N. Eleya, A. Mahal, M. Hein, A. Villinger, P. Langer, Adv. Synth. Catal. 2011, 353,

2761–2774.

[20] J. F. Hartwig, Acc. Chem. Res. 1998, 31, 852–860.

[21] a) J. R. Dehli, J. Legros, C. Bolm, Chem. Commun. 2005, 973–986; b) R. Frlan, D.

Kikelj, Synthesis 2006, 2006, 2271–2285; c) B. Schlummer, U. Scholz, Adv. Synth. Catal.

2004, 346, 1599–1626; d) M. A. Fernandez-Rodriguez, Q. Shen, J. F. Hartwig, J. Chem.

Soc. 2006, 128, 2180–2181; e) G. Bastug, S. P. Nolan, J. Org. Chem. 2013, 78, 9303–9308;

f) F. Tappe, V. Trepohl, M. Oestreich, Synthesis 2010, 2010, 3037–3062.

[22] J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald, Acc. Chem. Res. 1998, 31, 805–

818.

[23] a) E.-i. Negishi, J. Organomet. Chem. 2002, 653, 34–40; b) K. C. Nicolaou, P. G.

Bulger, D. Sarlah, Angew. Chem. Int. Ed. 2005, 44, 4442–4489; c) S. P. Stanforth,

Tetrahedron 1998, 54, 263–303.

[24] a) S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4544–

4568; b) S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–9695; c) A. J. J.

Lennox, G. C. Lloyd-Jones, Angew. Chem. Int. Ed. 2013, 52, 7362–7370; d) H. Li,

Johansson Seechurn, Carin C. C., T. J. Colacot, ACS Catal. 2012, 2, 1147–1164; e) R.

Rossi, F. Bellina, M. Lessi, Adv. Synth. Catal. 2012, 354, 1181–1255; f) M. Sasaki, H.

Fuwa, Synlett 2004, 1851–1874; g) M. Tobisu, N. Chatani, Angew. Chem. Int. Ed. 2009,

48, 3565–3568; h) V. Polshettiwar, A. Decottignies, C. Len, A. Fihri, ChemSusChem 2010,

3, 502–522; i) A. Suzuki, Chem. Commun. 2005, 4759–4763; j) A. Suzuki, Angew. Chem.

Int. Ed. 2011, 50, 6722–6737.

[25] a) R. Chinchilla, C. Najera, Chem. Rev. 2007, 107, 874–922; b) R. Chinchilla, C. Najera,

Chem. Soc. Rev. 2011, 40, 5084–5121; c) R. Chinchilla, C. Najera, Chem. Rev. 2014, 114,

1783–1826; d) K. Sonogashira, J. Organomet. Chem. 2002, 653, 46–49.

[26] X.-F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113, 1–35.

[27] Z. Liu, J. Wang, J. Org. Chem. 2013, 78, 10024–10030.

[28] Z. Shao, H. Zhang, Chem. Soc. Rev. 2012, 41, 560–572.

[29] Q. Xiao, Y. Zhang, J. Wang, Acc. Chem. Res. 2013, 46, 236–247.

[30] J. Barluenga, P. Moriel, C. Valdes, F. Aznar, Angew. Chem. Int. Ed. 2007, 46, 5587–

5590.

[31] J. Barluenga, C. Valdes, Angew. Chem. Int. Ed. 2011, 50, 7486–7500.

[32] a) G. A. Molander, J. P. Wolfe, M. Larhed, Cross coupling and Heck-type reactions,

Thieme, Stuttgart, 2013; b) J. P. Knowles, A. Whiting, Org. Biomol. Chem. 2007, 5, 31–

44.

[33] a) L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Chem. Soc. 2006, 128, 581–590;

b) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–238; c) G. P.

McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009, 38, 2447–2464.

[34] a) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem. Int. Ed.

2012, 51, 10236–10254; b) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936–

946.

APPENDIX

lxxxi

[35] L.-C. Campeau, K. Fagnou, Chem. Commun. 2006, 1253–1264.

[36] A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 1998, 37, 3387–3388.

[37] D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120, 9722–9723.

[38] a) R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461–1473; b) D. S. Surry, S.

L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338–6361; c) D. S. Surry, S. L. Buchwald,

Chem. Sci. 2011, 2, 27–50; d) A. Aranyos, D. W. Old, A. Kiyomori, J. P. Wolfe, J. P.

Sadighi, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 4369–4378.

[39] A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. Int. Ed. 2000, 39, 4153–4155.

[40] a) A. Zapf, M. Beller, Chem. Commun. 2005, 431–440; b) J. P. Stambuli, S. R. Stauffer,

K. H. Shaughnessy, J. F. Hartwig, J. Am. Chem. Soc. 2001, 123, 2677–2678.

[41] a) M.-N. Birkholz, Z. Freixa, van Leeuwen, Piet W N M, Chem. Soc. Rev. 2009, 38,

1099–1118; b) P. Dierkes, van Leeuwen, Piet W. N. M., J. Chem. Soc., Dalton Trans. 1999,

1519–1530; c) M. Kranenburg, van der Burgt, Yuri E. M., P. C. J. Kamer, van Leeuwen,

Piet W. N. M., K. Goubitz, J. Fraanje, Organometallics 1995, 14, 3081–3089; d) L. Qiu, F.

Y. Kwong, J. Wu, W. H. Lam, S. Chan, W.-Y. Yu, Y.-M. Li, R. Guo, Z. Zhou, A. S. C.

Chan, J. Chem. Soc. 2006, 128, 5955–5965; e) van Leeuwen, Piet W. N. M., P. C. J. Kamer,

J. N. H. Reek, P. Dierkes, Chem. Rev. 2000, 100, 2741–2770.

[42] a) L.-F. Tietze, Domino reactions, Wiley-VCH, Weinheim, 2013; b) L.-F. Tietze, G.

Brasche, K. M. Gericke, Domino reactions in organic synthesis, Wiley-VCH, Weinheim,

2006.

[43] L.-Q. Lu, J.-R. Chen, W.-J. Xiao, Acc. Chem. Res. 2012, 45, 1278–1293.

[44] a) M. Shiri, Chem. Rev. 2012, 112, 3508–3549; b) A. J. Kochanowska-Karamyan, M.

T. Hamann, Chem. Rev. 2010, 110, 4489–4497.

[45] G. W. Gribble, J. Chem. Soc., Perkin Trans. 1 2000, 1045–1075.

[46] S. Wagaw, B. H. Yang, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120, 6621–6622.

[47] a) J. Barluenga, F. Rodriguez, F. J. Fananas, Chem. Asian. J. 2009, 4, 1036–1048; b) S.

Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–2920; c) G. R. Humphrey, J. T. Kuethe,

Chem. Rev. 2006, 106, 2875–2911; d) M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29–41;

e) K. Krüger, A. Tillack, M. Beller, Adv. Synth. Catal. 2008, 350, 2153–2167.

[48] R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689–6690.

[49] A. Antonio, C. Sandro, M. Fabio, Tetrahedron Lett. 1992, 33, 3915–3918.

[50] M. G. Saulnier, D. B. Frennesson, M. S. Deshpande, D. M. Vyas, Tetrahedron Lett.

1995, 36, 7841–7844.

[51] L. Ackermann, Org. Lett. 2005, 7, 439–442.

[52] L. T. Kaspar, L. Ackermann, Tetrahedron 2005, 61, 11311–11316.

[53] M. C. Willis, G. N. Brace, I. P. Holmes, Angew. Chem. Int. Ed. 2005, 44, 403–406.

[54] J. Barluenga, A. Jimenez-Aquino, F. Aznar, C. Valdes, J. Chem. Soc. 2009, 131, 4031–

4041.

[55] A. W. Schmidt, K. R. Reddy, H.-J. Knolker, Chem. Rev. 2012, 112, 3193–3328.

APPENDIX

lxxxii

[56] a) K. Nozaki, K. Takahashi, K. Nakano, T. Hiyama, H.-Z. Tang, M. Fujiki, S.

Yamaguchi, K. Tamao, Angew. Chem. Int. Ed. 2003, 42, 2051–2053; b) Y. Zhou, J. G.

Verkade, Adv. Synth. Catal. 2010, 352, 616–620.

[57] a) L. Ackermann, A. Althammer, Angew. Chem. Int. Ed. 2007, 46, 1627–1629; b) L.

Ackermann, A. Althammer, P. Mayer, Synthesis 2009, 2009, 3493–3503.

[58] H. Kang, W. Fenical, J. Org. Chem. 1997, 62, 3254–3262.

[59] a) R. J. Andersen, D. J. Faulkner, C. H. He, G. D. van Duyne, J. Clardy, J. Am. Chem.

Soc. 1985, 107, 5492–5495; b) N. Lindquist, W. Fenical, G. D. van Duyne, J. Clardy, J.

Org. Chem. 1988, 53, 4570–4574.

[60] H. Fan, J. Peng, M. T. Hamann, J.-F. Hu, Chem. Rev. 2008, 108, 264–287.

[61] a) H. Kamiyama, Y. Kubo, H. Sato, N. Yamamoto, T. Fukuda, F. Ishibashi, M. Iwao,

Bioorg. Med. Chem. 2011, 19, 7541–7550; b) M. V. Reddy, M. R. Rao, D. Rhodes, M. S.

Hansen, K. Rubins, F. D. Bushman, Y. Venkateswarlu, D. J. Faulkner, J. Med. Chem. 1999,

42, 1901–1907; c) C. Ridley, Bioorg. Med. Chem. 2002, 10, 3285–3290.

[62] a) T. Ohta, T. Fukuda, F. Ishibashi, M. Iwao, J. Org. Chem. 2009, 74, 8143–8153; b) C.

Tardy, M. Facompre, W. Laine, B. Baldeyrou, D. Garcia-Gravalos, A. Francesch, C.

Mateo, A. Pastor, J. A. Jimenez, I. Manzanares et al., Bioorg. Med. Chem. 2004, 12, 1697–

1712.

[63] M. Iwao, T. Fukuda, F. Ishibashi, Heterocycles 2011, 83, 491.

[64] M. Komatsubara, T. Umeki, T. Fukuda, M. Iwao, J. Org. Chem. 2014, 79, 529–537.

[65] a) P. Cironi, I. Manzanares, F. Albericio, M. Alvarez, Org. Lett. 2003, 5, 2959–2962;

b) F. Ishibashi, S. Tanabe, T. Oda, M. Iwao, J. Nat. Prod. 2002, 65, 500–504.

[66] a) M. Zeeshan, V. O. Iaroshenko, S. Dudkin, D. M. Volochnyuk, P. Langer,

Tetrahedron Lett. 2010, 51, 3897–3898; b) O. Fatunsin, V. Iaroshenko, S. Dudkin, M.

Shkoor, D. Volochnyuk, A. Gevorgyan, P. Langer, Synlett 2010, 2010, 1533–1535.

[67] a) K. Cariou, B. Ronan, S. Mignani, L. Fensterbank, M. Malacria, Angew. Chem. Int.

Ed. 2007, 46, 1881–1884; b) K. Hiroya, S. Itoh, M. Ozawa, Y. Kanamori, T. Sakamoto,

Tetrahedron Lett. 2002, 43, 1277–1280; c) T. Kurisaki, T. Naniwa, H. Yamamoto, H.

Imagawa, M. Nishizawa, Tetrahedron Lett. 2007, 48, 1871–1874; d) X. Li, A. R. Chianese,

T. Vogel, R. H. Crabtree, Org. Lett. 2005, 7, 5437–5440; e) N. Sakai, K. Annaka, T.

Konakahara, Tetrahedron Lett. 2006, 47, 631–634; f) B. M. Trost, A. McClory, Angew.

Chem. Int. Ed. 2007, 46, 2074–2077; g) Y. Yin, Z. Chai, W.-Y. Ma, G. Zhao, Synthesis

2008, 2008, 4036–4040; h) Y. Zhang, J. P. Donahue, C.-J. Li, Org. Lett. 2007, 9, 627–630.

[68] L. Chen, M.-H. Xu, Adv. Synth. Catal. 2009, 351, 2005–2012.

[69] Z.-Y. Tang, Q.-S. Hu, Adv. Synth. Catal. 2006, 348, 846–850.

[70] L. Zhang, T. Meng, R. Fan, J. Wu, J. Org. Chem. 2007, 72, 7279–7286.

[71] a) M. Pohanka, Expert Opin. Ther. Pat. 2012, 22, 871–886; b) M. Weinstock, CNS

Drugs 1999, 12, 307–323.

[72] a) M. B. H. Youdim, D. Edmondson, K. F. Tipton, Nat. Rev. Neurosci. 2006, 7, 295–

309; b) M. Bortolato, K. Chen, J. C. Shih, Adv. Drug. Deliv. Rev. 2008, 60, 1527–1533.

APPENDIX

lxxxiii

[73] a) X. Zhou, X.-B. Wang, T. Wang, L.-Y. Kong, Bioorg. Med. Chem. 2008, 16, 8011–

8021; b) A. Saeed, S. Zaib, S. Ashraf, J. Iftikhar, M. Muddassar, K. Y. J. Zhang, J. Iqbal,

Bioorg. Chem. 2015, 63, 58–63; c) X. He, Y.-Y. Chen, J.-B. Shi, W.-J. Tang, Z.-X. Pan,

Z.-Q. Dong, B.-A. Song, J. Li, X.-H. Liu, Bioorg. Med. Chem. 2014, 22, 3732–3738; d) M.

Huang, S.-S. Xie, N. Jiang, J.-S. Lan, L.-Y. Kong, X.-B. Wang, Bioorg. Med. Chem. Lett.

2015, 25, 508–513; e) I. Orhan, H. Gulcan, Curr. Top. Med. Chem. 2015, 15, 1673–1682;

f) L. Pisani, R. Farina, M. Catto, R. M. Iacobazzi, O. Nicolotti, S. Cellamare, G. F.

Mangiatordi, N. Denora, R. Soto-Otero, L. Siragusa et al., J. Med. Chem. 2016, 59, 6791–

6806; g) A. Prasopthum, P. Pouyfung, S. Sarapusit, E. Srisook, P. Rongnoparut, Drug

Metab. Pharmacokinet. 2015, 30, 174–181; h) B.-F. Ruan, H.-J. Cheng, J. Ren, H.-L. Li,

L.-L. Guo, X.-X. Zhang, C. Liao, Eur. J. Med. Chem. 2015, 103, 185–190; i) P. O. Patil, S.

B. Bari, S. D. Firke, P. K. Deshmukh, S. T. Donda, D. A. Patil, Bioorg. Med. Chem. 2013,

21, 2434–2450.

[74] a) T. Ishikawa, Med. Res. Rev. 2001, 21, 61–72; b) T. Ishikawa, H. Ishii, Heterocycles

1999, 50, 627; c) V. Simánek, Z. Dvorák, V. Kubán, B. Klejdus, J. Vicar, J. Ulrichová, J.

Hlavac, Heterocycles 2006, 68, 2403.

[75] S. D. Phillips, R. N. Castle, J. Heterocycl. Chem. 1981, 18, 223–232.

[76] D. Glick (Ed.) Methods of Biochemical Analysis, John Wiley & Sons, Inc, Hoboken,

NJ, USA, 1971.

[77] A. M. Almerico, F. Mingoia, P. Diana, P. Barraja, A. Montalbano, A. Lauria, R. Loddo,

L. Sanna, D. Delpiano, M. G. Setzu et al., Eur. J. Med. Chem. 2002, 37, 3–10.

[78] a) V. Abet, A. Nunez, F. Mendicuti, C. Burgos, J. Alvarez-Builla, J. Org. Chem. 2008,

73, 8800–8807; b) E. Ahmed, A. L. Briseno, Y. Xia, S. A. Jenekhe, J. Chem. Soc. 2008,

130, 1118–1119; c) S. L. Bondarev, V. N. Knyukshto, S. A. Tikhomirov, A. N. Pyrko, Opt.

Spectrosc. 2006, 100, 386–393; d) A. Mishra, P. Bauerle, Angew. Chem. Int. Ed. 2012, 51,

2020–2067.

[79] C. Ritchie, G. J. T. Cooper, Y.-F. Song, C. Streb, H. Yin, A. D. C. Parenty, D. A.

MacLaren, L. Cronin, Nat. Chem. 2009, 1, 47–52.

[80] C. Baik, D. Kim, M.-S. Kang, K. Song, S. O. Kang, J. Ko, Tetrahedron 2009, 65, 5302–

5307.

[81] a) N. P. Buu-Hoï, P. Jacquignon, C. T. Long, J. Chem. Soc. 1957, 0, 505–509; b) D. Li,

B. Zhao, E. J. LaVoie, J. Org. Chem. 2000, 65, 2802–2805; c) M. Lysén, J. L. Kristensen,

P. Vedsø, M. Begtrup, Org. Lett. 2002, 4, 257–259; d) J. Pawlas, M. Begtrup, Org. Lett.

2002, 4, 2687–2690.

[82] C. Xie, Y. Zhang, Z. Huang, P. Xu, J. Org. Chem. 2007, 72, 5431–5434.

[83] L. Yan, D. Zhao, J. Lan, Y. Cheng, Q. Guo, X. Li, N. Wu, J. You, Org. Biomol. Chem.

2013, 11, 7966–7977.

[84] T. Satoh, M. Miura, D. Takeda, K. Hirano, Heterocycles 2012, 86, 487.

[85] C. Chen, G. Shang, J. Zhou, Y. Yu, B. Li, J. Peng, Org. Lett. 2014, 16, 1872–1875.

[86] J. Gao, Y. Shao, J. Zhu, J. Zhu, H. Mao, X. Wang, X. Lv, J. Org. Chem. 2014, 79, 9000–

9008.

APPENDIX

lxxxiv

[87] a) P. M. Byers, J. I. Rashid, R. K. Mohamed, I. V. Alabugin, Org. Lett. 2012, 14, 6032–

6035; b) T. Ishida, S. Kikuchi, T. Tsubo, T. Yamada, Org. Lett. 2013, 15, 848–851; c) M.

Kuhn, F. C. Falk, J. Paradies, Org. Lett. 2011, 13, 4100–4103; d) K. Yoshida, T. Furuyama,

C. Wang, A. Muranaka, D. Hashizume, S. Yasuike, M. Uchiyama, J. Org. Chem. 2012, 77,

729–732.

[88] a) T. Wang, Z. Yin, Z. Zhang, J. A. Bender, Z. Yang, G. Johnson, Z. Yang, L. M.

Zadjura, C. J. D'Arienzo, D. DiGiugno Parker et al., J. Med. Chem. 2009, 52, 7778–7787;

b) T. Wang, Z. Yang, Z. Zhang, Y.-F. Gong, K. A. Riccardi, P.-F. Lin, D. D. Parker, S.

Rahematpura, M. Mathew, M. Zheng et al., Bioorg. Med. Chem. Lett. 2013, 23, 213–217;

c) S. P. Tanis, M. B. Plewe, T. W. Johnson, S. L. Butler, D. Dalvie, D. DeLisle, K. R. Dress,

Q. Hu, B. Huang, J. E. Kuehler et al., Bioorg. Med. Chem. Lett. 2010, 20, 7429–7434; d)

M. B. Plewe, S. L. Butler, K. R. Dress, Q. Hu, T. W. Johnson, J. E. Kuehler, A. Kuki, H.

Lam, W. Liu, D. Nowlin et al., J. Med. Chem. 2009, 52, 7211–7219.

[89] S. J. Jung, G. Y. Kim, J. U. Lee, S. J. Eum, J. D. Lee, KR20150027659.

[90] S. R. Meech, D. Phillips, J. Photochem. 1983, 23, 193–217.

[91] N. Bontemps, F. Gattacceca, C. Long, O. P. Thomas, B. Banaigs, J. Nat. Prod. 2013,

76, 1801–1805.

[92] K. Venkateswarlu, K. Suneel, B. Das, K. N. Reddy, T. S. Reddy, Synth. Commun. 2008,

39, 215–219.

[93] a) R. F. Heck, Acc. Chem. Res. 1979, 12, 146–151; b) T. Mizoroki, K. Mori, A. Ozaki,

Bull. Chem. Soc. Jpn. 1971, 44, 581; c) L. Yin, J. Liebscher, Chem. Rev. 2007, 107, 133–

173; d) A. Biffis, M. Zecca, M. Basato, J. Mol. Catal. A: Chem. 2001, 173, 249–274; e) W.

Cabri, I. Candiani, Acc. Chem. Res. 1995, 28, 2–7.

[94] a) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009–3066; b) A. B.

Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945–2964; c) S. E. Gibson, R. J.

Middleton, Contemp. Org. Synth. 1996, 3, 447–471; d) G. A. Molander, J. P. Wolfe, M.

Larhed, Cross coupling and Heck-type reactions, Thieme, Stuttgart, 2013.

[95] G. Poli, G. Giambastiani, A. Heumann, Tetrahedron 2000, 56, 5959–5989.

[96] a) S. Y. Lau, N. G. Andersen, B. A. Keay, Org. Lett. 2001, 3, 181–184; b) S. P.

Maddaford, N. G. Andersen, W. A. Cristofoli, B. A. Keay, J. Am. Chem. Soc. 1996, 118,

10766–10773; c) Z. Owczarczyk, F. Lamaty, E. J. Vawter, E. Negishi, J. Am. Chem. Soc.

1992, 114, 10091–10092; d) A. C. Albéniz, P. Espinet, Y.-S. Lin, J. Am. Chem. Soc. 1996,

118, 7145–7152; e) D. Balcells, F. Maseras, B. A. Keay, T. Ziegler, Organometallics 2004,

23, 2784–2796.

[97] a) F. E. Meyer, P. J. Parsons, A. de Meijere, J. Org. Chem. 1991, 56, 6487–6488; b) D.

Soorukram, P. Knochel, Org. Lett. 2007, 9, 1021–1023.

[98] a) J. Barluenga, L. Florentino, F. Aznar, C. Valdes, Org. Lett. 2011, 13, 510–513; b) J.

R. Fulton, V. K. Aggarwal, J. de Vicente, Eur. J. Org. Chem. 2005, 2005, 1479–1492.

[99] a) R. Barroso, M.-P. Cabal, R. Badía-Laiño, C. Valdés, Chem. Eur. J. 2015, 21, 16463–

16473; b) R. Barroso, R. A. Valencia, M.-P. Cabal, C. Valdés, Org. Lett. 2014, 16, 2264–

2267.

APPENDIX

lxxxv

[100] a) J. E. Anthony, Chem. Rev. 2006, 106, 5028–5048; b) T. A. Grese, L. D. Pennington,

J. P. Sluka, M. D. Adrian, H. W. Cole, T. R. Fuson, D. E. Magee, D. L. Phillips, E. R.

Rowley, P. K. Shetler et al., J. Med. Chem. 1998, 41, 1272–1283; c) H.-J. Knölker, K. R.

Reddy, Chem. Rev. 2002, 102, 4303–4428; d) M. J. Rospondek, L. Marynowski, M. Góra,

Org. Geochem. 2007, 38, 1729–1756; e) D. R. Boyd, N. D. Sharma, F. Hempenstall, M. A.

Kennedy, J. F. Malone, C. C. R. Allen, S. M. Resnick, D. T. Gibson, J. Org. Chem. 1999,

64, 4005–4011.

[101] a) R. Che, Z. Wu, Z. Li, H. Xiang, X. Zhou, Chem. Eur. J. 2014, 20, 7258–7261; b)

C.-C. Chen, C.-M. Chen, M.-J. Wu, J. Org. Chem. 2014, 79, 4704–4711; c) G. Ferrara, T.

Jin, M. Akhtaruzzaman, A. Islam, L. Han, H. Jiang, Y. Yamamoto, Tetrahedron Lett. 2012,

53, 1946–1950; d) G. Ferrara, T. Jin, K. Oniwa, J. Zhao, A. M. Asiri, Y. Yamamoto,

Tetrahedron Lett. 2012, 53, 914–918; e) K. Hirano, Y. Inaba, N. Takahashi, M. Shimano,

S. Oishi, N. Fujii, H. Ohno, J. Org. Chem. 2011, 76, 1212–1227.

[102] M. Prashad, Y. Liu, X. Y. Mak, D. Har, O. Repič, T. J. Blacklock, Tetrahedron Lett.

2002, 43, 8559–8562.

[103] a) T. Dang, N. Kelzhanova, Z. Abilov, M. Turmukhanova, P. Langer, Synlett 2012, 23,

1283–1290; b) P. Langer, Chem. Eur. J. 2001, 7, 3858–3866; c) P. Langer, Synthesis 2002,

2002, 441–459; d) P. Langer, M. Döring, Eur. J. Org. Chem. 2002, 2002, 221–234; e) P.

Langer, W. Freiberg, Chem. Rev. 2004, 104, 4125–4150.

[104] a) D. Barnes-Seeman, J. Beck, C. Springer, Curr. Top. Med. Chem. 2014, 14, 855–864;

b) H.-J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller, U. Obst-Sander, M.

Stahl, Chembiochem 2004, 5, 637–643; c) K. L. Kirk, Org. Process Res. Dev. 2008, 12,

305–321; d) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008,

37, 320–330.

[105] P. M. Ridker, E. Danielson, F. A. H. Fonseca, J. Genest, A. M. Gotto, JR, J. J. P.

Kastelein, W. Koenig, P. Libby, A. J. Lorenzatti, J. G. MacFadyen et al., N. Engl. J. Med.

2008, 359, 2195–2207.

[106] a) N. Afdhal, K. R. Reddy, D. R. Nelson, E. Lawitz, S. C. Gordon, E. Schiff, R. Nahass,

R. Ghalib, N. Gitlin, R. Herring et al., N. Engl. J. Med. 2014, 370, 1483–1493; b) N. Afdhal,

S. Zeuzem, P. Kwo, M. Chojkier, N. Gitlin, M. Puoti, M. Romero-Gomez, J.-P. Zarski, K.

Agarwal, P. Buggisch et al., N. Engl. J. Med. 2014, 370, 1889–1898; c) E. J. Gane, C. A.

Stedman, R. H. Hyland, X. Ding, E. Svarovskaia, W. T. Symonds, R. G. Hindes, M. M.

Berrey, N. Engl. J. Med. 2013, 368, 34–44; d) E. Lawitz, A. Mangia, D. Wyles, M.

Rodriguez-Torres, T. Hassanein, S. C. Gordon, M. Schultz, M. N. Davis, Z. Kayali, K. R.

Reddy et al., N. Engl. J. Med. 2013, 368, 1878–1887.

[107] a) J. C. Biffinger, H. W. Kim, S. G. DiMagno, Chembiochem 2004, 5, 622–627; b) P.

Kirsch, Modern fluoroorganic chemistry, Wiley-VCH, Weinheim, Great Britain, 2013.

[108] a) S. Fustero, M. Sánchez-Roselló, P. Barrio, A. Simón-Fuentes, Chem. Rev. 2011, 111,

6984–7034; b) J.-Y. Yoon, S.-g. Lee, H. Shin, Curr. Org. Chem. 2011, 15, 657–674.

[109] H. A. DeWald, S. Lobbestael, B. P. H. Poschel, J. Med. Chem. 1981, 24, 982–987.

[110] N. K. Terrett, A. S. Bell, D. Brown, P. Ellis, Bioorg. Med. Chem. Lett. 1996, 6, 1819–

1824.

[111] M. Kim, C. Sim, D. Shin, E. Suh, K. Cho, Crop Prot. 2006, 25, 542–548.

APPENDIX

lxxxvi

[112] a) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470–477; b) P. Jeschke,

Chembiochem 2004, 5, 571–589; c) K. Muller, C. Faeh, F. Diederich, Science 2007, 317,

1881–1886; d) D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480, 224–228; e) O. A.

Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475–4521.

[113] M. A. Chowdhury, K. R. A. Abdellatif, Y. Dong, D. Das, M. R. Suresh, E. E. Knaus, J.

Med. Chem. 2009, 52, 1525–1529.

[114] S. R. Cox, S. Liao, M. Payne-Johnson, R. J. Zielinski, M. R. Stegemann, J. Vet.

Pharmacol. Ther. 2011, 34, 1–11.

[115] D. Zhang, N. Raghavan, S.-Y. Chen, H. Zhang, M. Quan, L. Lecureux, L. M. Patrone,

P. Y. S. Lam, S. J. Bonacorsi, R. M. Knabb et al., Drug Metab. Dispos. 2008, 36, 303–315.

[116] B. D. Maxwell, J. Labelled Cpd. Radiopharm. 2000, 43, 645–654.

[117] A. K. Culbreath, T. B. Brenneman, R. C. Kemerait, JR, G. G. Hammes, Pest. Manag.

Sci. 2009, 65, 66–73.

[118] a) S. Hernández, I. Moreno, R. SanMartin, G. Gómez, M. T. Herrero, E. Domínguez, J.

Org. Chem. 2010, 75, 434–441; b) P. S. Humphries, J. M. Finefield, Tetrahedron Lett.

2006, 47, 2443–2446; c) R. R. Ranatunge, M. Augustyniak, U. K. Bandarage, R. A. Earl,

J. L. Ellis, D. S. Garvey, D. R. Janero, L. G. Letts, A. M. Martino, M. G. Murty et al., J.

Med. Chem. 2004, 47, 2180–2193; d) S. Fustero, R. Román, J. F. Sanz-Cervera, A.

Simón-Fuentes, J. Bueno, S. Villanova, J. Org. Chem. 2008, 73, 8545–8552.

[119] T. Eicher, S. Hauptmann, A. Speicher, The Chemistry of Heterocycles, Wiley-VCH,

Weinheim, FRG, 2003.

[120] J. C. Sloop, C. L. Bumgardner, W. Loehle, J. Fluor. Chem. 2002, 118, 135–147.

[121] L. Buriol, C. P. Frizzo, L. D. T. Prola, D. N. Moreira, M. R. B. Marzari, E. Scapin, N.

Zanatta, H. G. Bonacorso, M. A. P. Martins, Catal. Lett. 2011, 141, 1130–1135.

[122] S. Fustero, R. Román, J. F. Sanz-Cervera, A. Simón-Fuentes, A. C. Cuñat, S. Villanova,

M. Murguía, J. Org. Chem. 2008, 73, 3523–3529.

[123] E. Y. Slobodyanyuk, O. S. Artamonov, O. V. Shishkin, P. K. Mykhailiuk, Eur. J. Org.

Chem. 2014, 2014, 2487–2495.

[124] G. Ji, X. Wang, S. Zhang, Y. Xu, Y. Ye, M. Li, Y. Zhang, J. Wang, Chem. Commun.

2014, 50, 4361–4363.

[125] a) R. S. Foote, C. F. Beam, C. R. Hauser, J. Heterocycl. Chem. 1970, 7, 589–592; b) N.

Matsumura, A. Kunugihara, S. Yoneda, Tetrahedron Lett. 1983, 24, 3239–3242; c) T. T.

Dang, T. T. Dang, C. Fischer, H. Görls, P. Langer, Tetrahedron 2008, 64, 2207–2215; d)

T. T. Dang, T. T. Dang, P. Langer, Tetrahedron Lett. 2007, 48, 3591–3593; e) T. T. Dang,

T. T. Dang, P. Langer, Synlett 2011, 2633–2642.

[126] a) J. M. Bates, J. Akerlund, E. Mittge, K. Guillemin, Cell Host Microbe 2007, 2, 371–

382; b) J. Fawley, D. M. Gourlay, J. Surg. Res. 2016, 202, 225–234; c) J.-P. Lalles, Nutr.

Rev. 2010, 68, 323–332.

[127] M. I. Torres, P. Lorite, M. A. Lopez-Casado, A. Rios, Pathol. Res. Pract. 2007, 203,

485–487.

APPENDIX

lxxxvii

[128] a) H. Orimo, J. Nippon Med. Sch. 2010, 77, 4–12; b) M. P. Whyte, Endocr. Rev. 1994,

15, 439–461; c) J. E. Coleman, Annu. Rev. Biophys. Biomol. Struct. 1992, 21, 441–483.

[129] S. Sidique, R. Ardecky, Y. Su, S. Narisawa, B. Brown, J. L. Millan, E. Sergienko, N.

D. P. Cosford, Bioorg. Med. Chem. Lett. 2009, 19, 222–225.

[130] a) M. al-Rashida, J. Iqbal, Med. Res. Rev. 2014, 34, 703–743; b) Y. Baqi, Mini-Rev.

Med. Chem. 2015, 15, 21–33; c) M. Rashida, J. Iqbal, Mini-Rev. Med. Chem. 2015, 15, 41–

51.

Publication list

1. T. N. Ngo, T. T. Dang, A. Villinger, P. Langer, Adv. Synth. Catal. 2016, 358, 1328–1336.

2. H. Do, H. Tran, L. Ohlendorf, T. N. Ngo, T. Dang, P. Ehlers, A. Villinger, P. Langer,

Synlett 2015, 26, 2429–2433.

3. T. Q. Hung, T. N. Ngo, D. H. Hoang, T. T. Dang, K. Ayub, A. Villinger, S. Lochbrunner,

G.-U. Flechsig, P. Langer, Eur. J. Org. Chem. 2015, 2015, 1007–1019.

4. T. N. Ngo, O. A. Akrawi, T. T. Dang, A. Villinger, P. Langer, Tetrahedron Lett. 2015, 56,

86–88.

5. T. N. Ngo, F. Janert, P. Ehlers, D. H. Hoang, T. T. Dang, A. Villinger, S. Lochbrunner, P.

Langer, Org. Biomol. Chem. 2016, 14, 1293–1301.

6. T. N. Ngo, P. Ehlers, T. T. Dang, A. Villinger, P. Langer, Org. Biomol. Chem. 2015, 13,

3321–3330.

7. T. N. Ngo, S. A. Ejaz, T. Q. Hung, T. T. Dang, J. Iqbal, J. Lecka, J. Sevigny, P. Langer,

Org. Biomol. Chem. 2015, 13, 8277–8290.

8. N. N. Pham, T. T. Dang, T. N. Ngo, A. Villinger, P. Ehlers, P. Langer, Org. Biomol. Chem.

2015, 13, 6047–6058.

9. T. Q. Hung, D. H. Hoang, T. N. Ngo, T. T. Dang, K. Ayub, A. Villinger, A. Friedrich, S.

Lochbrunner, G.-U. Flechsig, P. Langer, Org. Biomol. Chem. 2014, 12, 6151–6166.

10. T. Q. Hung, T. N. Ngo, D. H. Hoang, T. T. Dang, A. Villinger, P. Langer, Org. Biomol.

Chem. 2014, 12, 2596–2605.

Documents

Synthesis of Aromatic Heterocycles by Palladium(0